Review ArticleMolecular Markers for Breast Cancer Prediction onTumor Behavior

Bruna Karina Banin Hirata Julie Massayo Maeda OdaRoberta Losi Guembarovski Carolina Batista Ariza Carlos Eduardo Coral de Oliveiraand Maria Angelica Ehara Watanabe

Laboratory of Polymorphism and Application Study of DNA Department of Pathological Sciences Biological Sciences CenterState University of Londrina 86057-970 Londrina Brazil

Correspondence should be addressed to Maria Angelica Ehara Watanabe maewatuelgmailcom

Received 24 June 2013 Revised 4 October 2013 Accepted 12 November 2013 Published 28 January 2014

Academic Editor Andreas Pich

Copyright copy 2014 Bruna Karina Banin Hirata et al This is an open access article distributed under the Creative CommonsAttribution License which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited

Breast cancer is one of the most common cancers with greater than 1300000 cases and 450000 deaths each year worldwideThe development of breast cancer involves a progression through intermediate stages until the invasive carcinoma and finallyinto metastatic disease Given the variability in clinical progression the identification of markers that could predict the tumorbehavior is particularly important in breast cancer The determination of tumor markers is a useful tool for clinical managementin cancer patients assisting in diagnostic staging evaluation of therapeutic response detection of recurrence and metastasisand development of new treatment modalities In this context this review aims to discuss the main tumor markers in breastcarcinogenesis The most well-established breast molecular markers with prognostic andor therapeutic value like hormonereceptors HER-2 oncogene Ki-67 and p53 proteins and the genes for hereditary breast cancer will be presented Furthermorethis review shows the new molecular targets in breast cancer CXCR4 caveolin miRNA and FOXP3 as promising candidates forfuture development of effective and targeted therapies also with lower toxicity

1 Introduction

The global importance of cancer is unquestionable consid-ered the second cause of death worldwide The incidenceof different cancers had increased both in developed and indeveloping countries as a result of increasing exposure to riskfactors and life expectancy [1] Breast cancer is one of themostcommon cancers withmore than 1300000 cases and 450000deaths each year worldwide [2] In Brazil 52680 new cases ofbreast cancer are expected for 2012 with an estimated risk of52 cases per 100000 women [3]

Breast tumors are classified histologically according tothe location of origin The ductal tumors develop in breastducts and represent 80 of tumors The lobular tumorsdevelop inside the lobes and account for 10 to 15 of casesOther subtypes represent less than 10 of cases diagnosedper year [4] Patients with invasive ductal carcinoma presenthigher lymphatic involvement and worse prognosis than less

common types of breast carcinoma [5] The staging systemwidely used is Tumor-Node-Metastasis (TNM) classificationof malignant tumors as recommended by the Union forInternational Cancer Control (UICC) which is an anatom-ically based system that records the primary and regionalnodal extent of the tumor and the absence or presence ofmetastases The evaluation of these parameters allows thedetermination of staging varying from stages 0 to IV [6]

The development of breast cancer involves a progressionthrough series of intermediate processes starting with ductalhyperproliferation followed by subsequent evolution to car-cinoma in situ invasive carcinoma and finally intometastaticdisease [7] Given the variability in clinical progression ofdisease the identification of markers that could predicttumor behavior is particularly important in breast cancerAlso the determination of tumor markers is a useful toolfor the clinical management of cancer patients assistingin diagnostic procedures staging evaluation of therapeutic

Hindawi Publishing CorporationDisease MarkersVolume 2014 Article ID 513158 12 pageshttpdxdoiorg1011552014513158

2 Disease Markers

response detection of recurrence and distant metastasis andprognosis [8] helping in the development of new treatmentmodalities [9]Therefore this review aims to discuss themaintumor markers for breast cancer development progressionand possible new therapeutic targets

2 Molecular Markers

According to US National Institutes of Healthrsquos (NIH)Working Group and Biomarkers Consortium a molecularmarker is a characteristic that is objectively measured as anindicator of pathogenic or normal biological processes or apharmacological response to a therapeutic intervention [10]Although the most of these markers is protein recently geneexpression patterns and altered DNA identified in tumortissue have also taken prominence as tumor markers [11]

It is known that breast cancer represents a complex andheterogeneous disease that comprises distinct pathologieshistological features and clinical outcome Also it is wellestablished that this neoplasia has well-defined molecularsubgroups based on gene expression profiling closely relatedto the behavior of these molecular subtypes Sotiriou andPusztai [12] pointed out that results from studies of gene-expression profiling have altered the view of breast cancerand provided a new tool for molecular diagnosis Actuallythe status of estrogen receptor (ER) progesterone receptor(PR) and human epidermal growth factor receptor type 2(HER2) has been used as predictive markers for identifyinga high-risk phenotype and for selection of the most efficienttherapies [13]

The heterogeneity of breast cancer was reflected in array-CGH (comparative genomic hybridization) data of severalreports demonstrating clear or less clear associations with itssubtypes [14] After the sequencing of human genome and thetechnical progress in protein identification it is reasonableconsidering an integrated program of genomics and pro-teomics to accomplish better comprehension of breast cancerfeatures and the development of improved therapeutics [15]Together these results strengthened evidence of improvedsensitivity and resolutionmethodologies which contribute tothe classification of breast cancer

Within this context in this review will be presented somewell-stablishedmolecular markers of therapeutic value in theprognosis of breast cancer and promising new markers notroutinely used in clinical practice

3 Well-Established Prognostic andorTherapeutic Breast Cancer Markers

31 Hormone Receptors (HR) Approximately more thanone million women are diagnosed with breast cancer eachyear and approximately 700000 of these have positive (+)hormone receptors (HR) [16] The hormone receptors areexpressed proteins both in the epithelium and in breaststroma which bind to circulating hormones mediating theircellular effects [17 18]

TheHRbest studied in breast cancer are estrogen receptor(ER) and progesterone receptors (PR) Breast cancers classi-fied by positive immunohistochemistry (IHC) expression ofER andPRhave different clinical pathological andmolecularcharacteristics [19] It is postulated that risk factors areclosely associated with breast tumors ER+ and PR+ andmay involve mechanisms related to exposure to estrogen andprogesterone while etiology of breast cancer ERminus and PRminusshould be independent of hormone exposure [20 21]The ERand PR are highly associated with patient age at diagnosisrising continuously with age

During the 1980s Tamoxifen became the first anti-estrogenic therapy targeted to ER for adjuvant therapy[22] The antagonist effects of this drug in breast tissuemay result from its ability to bind to the ligand-bindingdomain of ER effectively blocking the potential for estrogenstimulation Tamoxifen binding further prevents critical ERconformational changes that are required for the associationof coactivators [23]This therapy produced clinical remissionin patients with breast cancer positive for ER differently fromtumors with low or undetectable levels of these receptors[24] Additionally tumor cells expressing hormone receptorspresented a better response to hormone therapy and patientsdemonstrated higher survival both disease free as overall [2526] and better prognosis [27] Although hormone therapyhas revolutionized the management of breast cancer andresults have improved substantially in these patients theoptimal management remains a significant challenge

32 Human Epidermal Growth Factor Receptor 2 (HER-2)Several names has been given for this gene such as c-erb-2cerbB-2 C-erbB-2 HER-2 HER-2neu ERBB2 erbB2 erbB-2 neuc-erbB-2oncogene neu neu protein and neu [27]This reviewwill adopt the term ldquoHER-2rdquoTheHER-2 has beenextensively studied in breast cancer since Slamon et al [28]demonstrated an association between HER-2 amplificationand poor prognosis [29]

HER-2 is a transmembrane tyrosine kinase receptorbelonging to a family of epidermal growth factor receptorsstructurally related to epidermal growth factor receptor(EGFR) encoded by ERBB2HER2 oncogene located onchromosome 17q21 [30] This oncogene is amplified in 20to 30 of breast cancers and is considered a marker ofpoor prognosis once its overexpression is associated withan aggressive phenotype of tumor cells resistance to anti-hormonal cytotoxic therapies and low overall survival

In the cell signaling the homodimerization or het-erodimerization of HER family receptors activates intracel-lular tyrosine kinase domain which promotes the autophos-phorylation of tyrosine residues of cytoplasmatic tail andthus triggers pathways that results in survival and cellularproliferation [31] However according to crystallographicanalysis HER-2 is ready in binding conformation even in theabsence of ligand explaining why this receptor lacks naturalligands [32]

Currently the humanized monoclonal antibody Trastuz-umab directed against the extracellular domains of HER-2is indicated for the treatment of HER-2 positive breast cancer

Disease Markers 3

cases The efficacy of Trastuzumab as part of an antitumorprotocol has been validated in several clinical studies wherethis antibody showed inhibitory effect on tumor growthand chemotherapy sensitizer [33] Although the mechanismsby which Trastuzumab inhibits the signaling mediated byHER-2 are not fully understood its antitumor effects aresupposed to be conferred by inhibition of receptor-receptorinteraction receptor decreasing by endocytosis blockade ofextracellular domain cleavage of receptor and activation ofantibody-dependent cellular cytotoxicity (ADCC) [34 35]In addition to Trastuzumab other therapeutic strategies havebeen developed to target HER-2 protein such as tyrosinekinase inhibitor Lapatinib which showed improved efficacyafter failure of Trastuzumab therapy [36]

HER-2 status of breast cancer is routinely assessed byeither IHC analysis of HER-2 protein or fluorescent insitu hybridization (FISH) analysis of gene copy number inprimary tumor tissues It was shown that HER-2 extracellulardomain (ECD) can be shed into circulation by proteolyticcleavage from the full-length HER-2 receptor and it isdetected in serum of women with benign breast disease pri-mary andmetastatic breast cancer [37]The ldquosolublerdquo receptorcan be quantified by enzyme-linked immunoabsorbent assay(ELISA) method [38] Tan et al [39] established a Dot blotmethod to detect serum HER-2 levels which is a valid andinexpensive assay with potential application in monitoringbreast cancer progression in clinical situations

Although HER-2 is associated with aggressive form ofcancer a specific subgroup named triple negative breastcancer (TNBC) arouses special interest once they are orphanof directed treatment TNBC is a subtype characterized by thelack of ER PR andHER-2 expression and it is associatedwithyounger age at diagnosis [40] There is an exhaustive searcheffort to find the drivers of this breast cancer subtype becausethe usual antiendocrine and anti-HER2 targeted therapiesare ineffective and traditional cytotoxic chemotherapy seemsto be insufficient [41] The aggressive clinical course poorprognosis and lack of specific therapeutic options haveintensified current interest in this subtype of tumor [42]The clinical behavior of TNBC is classically more aggressivethan other types like luminal A and B molecular subtypesthat according to Soslashrlie et al [43] are considered of best andintermediate prognosis respectively

33 Ki 67 Antigen TheKi-67 antigen first described in 1983is a labile nonhistone nuclear protein that is tightly linked tothe cell cycle and is expressed inmid-G1 S G2 andM phasesof proliferating cells but not in quiescent or resting cells of theG0 and early G1 phases Ki-67 score is the most often mea-sured on histological sections by IHC methodology and isdefined as the percentage of stained invasive carcinoma cells[44 45] Vielh et al [46] demonstrated a strong correlationbetween phase S and Ki-67 and they verified that quantitativeevaluation of Ki-67 can offer a precise estimation of tumorproliferation index According to the St Gallen Consensusof 2011 the proliferation index is considered low or negativewhen there are 14 or less stained nuclei and it is considered

positive or high when there are more than 14 of stainednuclei [47]

Biological markers that can predict a clinic or pathologicresponse to primary systemic therapy of early form duringa cycle of chemotherapy can show considerable clinicalimportance Patil et al [48] evaluated Ki-67 index andapoptotic index (AI) before during and after neoadjuvantchemotherapy with anthracycline in indigenous woman withbreast cancer but found no significant differences

Tawfik et al [49] demonstrated for the first time that highexpression of Ki-67 in axillary lymph nodes but not in breasttissue is significantly associated with shorter patient survivalBased on this result patients with higher proliferative activityin lymph nodes metastases might require more aggressivetherapy and closer clinical monitoring of their disease

The prognostic and predictive value of Ki-67 was eval-uated in a review developed by Luporsi et al [50] andthey concluded that this biomarker could be considered asa prognostic factor for therapeutic decision however stan-dardization of techniques and scoring methods are neededfor integration of this biomarker in everyday practice

34 Tumor Protein p53 The p53 is involved in several criticalpathways including cell cycle arrest apoptosis DNA repairand cellular senescence which are essential for normalcellular homeostasis and genome integrity maintenanceAlteration of TP53 gene or posttranslational modificationin p53 protein can alter its response to cellular stress Themolecular archaeology of TP53mutation spectrum generateshypotheses concerning etiology and molecular pathogenesisof human cancer [51] In breast cancer approximately 30of patients display TP53 gene mutation but this frequencyfluctuates from more than 80 in basal-like to less than 15in luminal-A subtypes [52]

According to Allred et al [53] expression of mutantp53 protein was associated with high tumor proliferationrate early disease recurrence and early death in node-negative breast cancer Dumay et al [54] investigated TP53mutations in breast tumors from the luminal basal andmolecular apocrine molecular subgroups They found thatsubgroups differ not only in TP53 mutation frequency butalso in mutation types and consequences They detected ahigh prevalence ofmissensemutations in luminal tumors andtruncating mutations in basal tumors In apocrine moleculartumors despite high prevalence of insertionsdeletions p53truncation was not increased The observations point todifferent mutational mechanisms functional consequencesandor selective pressures in different breast cancers subtypes

Mutations in TP53 gene result in altered molecular con-formation and prolonged protein half-life leading to nuclearaccumulation of altered p53 proteinThe IHCmethod detectsthis abnormal accumulation and acts as an indirect indicativeof mutation in TP53 gene [55] This nuclear accumulationis an indicator of a poor clinical outcome for breast cancerpatients However despite its prognostic value there is stillno proper treatment that takes into account the status of thismarker

4 Disease Markers

35 Carbohydrate 15-3 and Carcinoembryonic Antigens (CA15-3 and CEA) Breast cancer is generally no longer curableonce metastases are detected by ldquoclassicalrdquo means clinicalmanifestations of the spread imaging methods and serummarker assays such as those based on carcinoma antigen 15-3 (CA 15-3) or carcinoembryonic antigen (CEA) [56]

CA 15-3 in combination with CEA is also relevant tumormarkers in breast cancer [57] According to Geraghty et al[58] the serum marker CA 15-3 has superior prognosticrelevance in relation to CEA but unlike these authorsEbeling et al [59] reported that prognostic value of CEA ishigher than that of CA 15-3 which demonstrated that thismarker has conflicting implications in breast carcinogenesis

The CEA is a glycoprotein which has been shown tobe expressed in vast majority of human colorectal gastricand pancreatic cancers as well as in breast carcinomas andnonsmall cell lung carcinomas [60] Determination of CEAin breast cancer is indicative of tumor size and nodal involve-ment Therefore CEA concentrations greater than 75120583gLare associated with high probability of subclinical metastases[61] Prognosis of patients whose CEA level was within thenormal range at the time of diagnosis is significantly betterthan those with elevated CEA levels [62]

CA 15-3 peptides are shed or soluble forms of MUC-1 which exists as a transmembrane protein consisting oftwo subunits that form a stable dimer The release has beenshown to be mediated by 2 proteases ADAM17 and MT-MMP1 [63 64] This is heterogeneously expressed on theapical surface of different normal epithelial cell types but itis aberrantly overexpressed in 90 of breast cancer [65]

Sandri et al [66] found a prognostic role for CA 15-3 within subgroups of patients with luminal B and HER-2 positive disease According to their results baseline CA15-3 might be value in the identification of higher risk ofrelapse where adjuvant chemotherapy must be introducedIn other words this study showed explicitly that presence ofan abnormal CA 15-3 presurgical value is associated with anincreased risk of recurrence and death Further studies usingdatabase analyses or prospective trials are required to confirmthe prognostic value of presurgery CA 15-3 determination inbreast cancer If confirmed the presence of elevated CA 15-3should be added to the list of features that must be taken intoaccount while making a proper treatment choice AccordingtoMendes et al [67] measurement of tumormarkers is a toolfor detection of distant metastases and the marker CA 15-3 seems more efficient when compared to CEA Monitoringof breast cancer patients after surgical treatment using onlythis tumor marker is insufficient However simultaneous useof both serum markers (CA 15-3 and CEA) allows the earlydiagnosis of metastasis in up to 60ndash80 of patients withbreast cancer [68]

36 Breast Cancer Susceptibility Genes (BRCA1 and BRCA2)Approximately 80 of the cases related to familial breastcancer are associated with one gene of hereditary suscep-tibility for breast and ovarian cancer BRCA1 and BRCA2The BRCA genes have been classified as tumour-suppressorgenes because the loss of wild-type allele has been observed

in tumors of heterozygous carriers BRCA proteins playimportant roles in different cellular processes including acti-vation and transcriptional regulation repair of DNAdamagebeyond the control of cell cycle cellular proliferation anddifferentiation [69 70]

Besides breast cancer these genes are associated with ele-vated risk of ovary prostate and pancreas cancers Howeverdespite its association with inherited predisposition somaticdisease-causingmutations in BRCA1 or BRCA2 are extremelyrare in sporadic breast cancer [71 72]

The frequency and spectrum of mutations within BRCA1or BRCA2 genes show considerable variation between ethnicgroup and geographic region probably due to interactionsbetween different lifestyle and genetic characteristics Studieshave discussed the role of maternal or paternal inheritanceof BRCA mutation affecting risk of breast cancer Shapiraet al [73] showed that lifetime risk was higher in BRCAmutation inherited from the father compared to the motherHowever in accordance to Senst et al [74] although therisk of breast cancer seems to be modestly higher in womenwith paternal BRCA1 mutation the results of the study werenot significant Thus data are not sufficiently compellingto justify different screening recommendations for the twosubgroups Furthermore parental mutation origin also didnot affect the risk in women with BRCA2mutation

Family history profiles can predict BRCA1 or BRCA2mutation mainly those characterized by first-degree relativeswith ovarian cancer or breast cancer along with young ageat diagnosis bilateral occurrence and increased number ofaffected relativesThese predictors would be useful in geneticcounseling and decision-making for a genetic test but they arestill of limited value since a considerable number of BRCA1or BRCA2 mutations are observed in breast cancer familieswithout such risk factors Definitive predictors need to bedeveloped in future studies [75]

Genetic counseling and genetic testing to identify BRCA1and BRCA2 gene mutations in high-risk patients are widelyavailable and commonly employed in the US and Europe [7677] Individuals who undergo genetic testing by sequencingtheirDNA for specific regions of these genes anddiscover thatthey carry a BRCAmutation can have the diagnosis of breastcancer anticipated and perhaps in some cases prevented Ifa high-risk status of these women had been recognized theymight have had the opportunity to choose genetic counselingtesting more effective cancer surveillance and potentiallypreventive options such as prophylactic surgery andorchemoprevention [78] Among these preventive optionsbilateral mastectomy although invasive reduces approxi-mately 90 the risk of breast cancer in women with BRCA12mutations [79]

According to Apostolou and Fostira [80] more suscep-tible genes have been discovered and BRCA1 and BRCA2predisposition seems to be only a part of the story Thesenew findings include rare germline mutations in otherhigh penetrant genes the most important between theminclude TP53 mutations in Li-Fraumeni syndrome STK11(serinethreonine kinase 11) mutations in Peutz-Jeghers syn-drome andPTEN (phosphatase and tensin homolog on chro-mosome ten) mutations in Cowden syndrome Furthermore

Disease Markers 5

more frequent but less penetrant mutations have been iden-tified in families with breast cancer clustering in moderateor low penetrant genes such as CHEK2 (checkpoint kinase2) ATM (ataxia telangiectasia mutated) PALB2 (partner andlocalizer of BRCA2) and BRIP1 (BRCA1-interacting proteinC-terminal helicase 1)

4 Future Candidate Markers forPrognosis and Therapeutic Responses inBreast Cancer Evolution

41 Proliferating Cell Nuclear Antigen (PCNA) Moldovan etal [81] have described the proliferating cell nuclear anti-gen (PCNA) as a nonhistone nuclear protein that forms ahomotrimeric ring encircling DNA double helix and actsas a molecular platform to recruit proteins involved inDNA synthesis such as DNA polymerase delta cell-cyclecontrol DNA-damage response and repair PCNA exists intwo distinct forms replication-competent chromatin-boundform and chromatin unbound form which is not involvedin DNA synthesis [82] For instance it is not clear howthese two populations of PCNA are regulated In a numberof tumors measurement of this protein was associated withmitotic activity and tumor grade [83] The PCNA signaltransduction has an important impact on growth regulationof breast cancer cells and is associated with poor overallsurvival [84] Recently it was reported that phosphorylationof PCNA at tyrosine 211 (Y211) is a promising treatment targetin prostate cancer [85] The results obtained by Zhao et al[84] suggested that targeting phospho-Y211 PCNA could bean effective strategy in breast cancer treatment as well in thefuture

42 Caveolin Studies showed that caveolae and caveolin1 play an essential role in many molecular cellular andphysiological processes [86] Caveolae are special invaginatedmicrodomains of the plasma membrane found in the major-ity of mammalian cells and serve as membrane organizingcentersThreemembers of caveolin family (CAV1 CAV2 andCAV3) have been identified and they play a pivotal role inintracellular trafficking of cellular components and in signaltransduction [87]

Recently it has been reported an strong associationbetween CAV1 and CAV2 expression and high histologicalgrade and lack of hormone receptors positivity (ER and PR)in basal-like breast cancer subtype [88] providing evidencethat these proteins can have oncogenic properties Aside frombreast association between caveolin expression and poorpatient outcomewas noticed in other tumor tissues includingprostate [89] lung [90] and central nervous system [91]

The caveolin 1 influences cancer formation progressionand prognosis but this influence is not so sharp in spiteof recent results that have clarified many roles Its role asoncoprotein or tumor suppressor may depend on interactionwith molecular signaling molecules by specific regions andthis may be modified by genetic changes mRNA andprotein expression level Current and future research intomechanisms by which caveolin 1 function in tumorigenesis

process will most likely lead to a new molecular markerin diagnosis and prognosis and even in treatment of breastcancer [86]

43 Receptor C-X-C Chemokine Receptor Type 4 (CXCR4)The CXCR4 is transmembrane G-coupled receptor proteinidentified as a coreceptor for T-cell line tropic strains ofhuman immunodeficiency virus [92] Its role in breast cancermetastasis was first documented in 2001 [93]

This receptor is required for migration of breast cancercells from the primary site to lung bones and lymph nodeswhich represent organs that secrete high levels of chemokineCXCL12 For this reason CXCR4 has been found to be aprognostic marker in breast cancer among other types ofcancer [94]

Schioppa et al [95] made an important observation thatthe expression of CXCR4 is up-regulated in tumor cellsresulting from a change in tumor microenvironment Tumorcells cultured in hypoxic conditions for example showedsignificant overexpression of CXCR4

The expression level of CXCR4 is significantly corre-lated with lymph node metastasis [96] Patients who hadCXCR4 overexpression had significantly higher incidenceof cancer recurrence and cancer-related deaths than thosein low CXCR4 expression group [97] Its expression alsois significantly related to tumor size advanced TNM stageand shorter overall- and disease-free survival However inluminal or HER2-positive breast cancer groups CXCR4 wasnot correlated with such clinic-pathological characteristicsand survival This association is cardinal in TNBC patientswho expressed high levels of CXCR4 which have poorerdisease-free survival and overall survival compared withTNBC patients expressing low levels of this marker [98]These findings indicated that CXCR4 high expression inTNBC might indicate a more aggressive tumor phenotype

Therefore this receptor may be a potential therapeutictarget in cancer therapies for breast cancer So far the beststudied among the compounds that inhibit CXCR4-CXCL12interaction is the antagonist AMD3100 This compoundsignificantly inhibits the invasion and metastasis activity ofcancer cells [99]

44 Chemokine (C-C Motif) Ligands 2 and 5 (CCL2 andCCL5) Many studies have addressed the involvement androles of inflammatory chemokines CCL2 (MCP-1 mem-brane cofactor protein-1) and CCL5 (RANTES regulated onactivation normal T-cell expressed and secreted) in breastmalignancy Belonging to chemokine super family CCL2and CCL5 are well recognized because of their activities inthe immune context where they induce leukocyte directedmotility Acting mainly in inflammatory reactions these twochemokines stimulate migration primarily of monocytes andT-cells to damaged or infected sites [100ndash102]

Some studies have shown that CCL2 and CCL5 expres-sions are higher in breast cancer tissue than in correspondingnormal tissue [103 104] CCL2 has been correlated withhigher tumor grade and has been shown to have signifi-cant prognostic value for relapse-free survival The CCL2

6 Disease Markers

likely exerts its protumorigenic effects through recruitmentof tumor-associated macrophages and angiogenesis [105]Furthermore CCL2CCR2 (CCL2 receptor) chemokine sig-naling seems to be implicated in cell migration and itsoverexpression is associated with breast cancer metastasis toboth lung and bone [104 106]

TheCCL5CCR5 (CCL5 receptor) axis is active in patientsaffected by aggressive basal subtype of breast cancerMurookaet al [107] showed that CCL5 enhancedMCF-7 (breast cancercell lines) proliferation Furthermore according to Velasco-Velazquez and Pestell [108] CCR5 promoted breast cancerinvasiveness and metastatic potential These results indi-cated that CCL5 expression is directly correlated with moreadvanced stage of disease emphasizing their involvement inbreast cancer progression [109] In this context these twochemokines could be considered as prognostic markers andtherapeutic targets for breast cancer

45 Growth Factors EGF HGF IGF VEGF and TGF-120573 Therole of growth factors has been extensively analyzed both incancer risk and tumor progression Cerna et al [110] founda negative correlation between insulin-like growth factorI (IGF1) and severity of cancer Thus according to theseauthors this growth factor cannot be used for quick andcorrect orientation in clinical condition of patients in theearly stages of tumor growth unlike epidermal growth factor(EGF) Nevertheless the IGF1 and EGF are stimuli to migra-tion of cancer cells to distant areas to form metastasis andhave been implicated in the development and progression ofhuman breast carcinoma [111]

The hepatocyte growth factor (HGF) is considered aprogression and aggressiveness marker of breast cancer anddata obtained by Kucera et al [112] fully corresponds to thisBased on their data this marker could potentially be usedas an additional tool for the differentiation between benignand malignant tumor Ahmed et al [113] also demonstratedthat serum levels of HGF may help in the diagnosis of breastcancer patients and may aid in disease prognosis HoweverCerna et al [110] related the opposite for HGF as well asIGF1 and vascular endothelial growth factor (VEGF) It wasdemonstrated that tumor stromal VEGF-A expression is avaluable prognostic indicator of breast cancer-specific anddisease-free survival at diagnosis and can therefore be usedto stratify patients with inflammatory breast cancer (IBC)into low-risk and high-risk groups for death and relapsesFurthermore high levels of tumor stromal VEGF-A maybe useful to identify IBC patients who will benefit fromantiangiogenic treatment since VEGF-A is the most potentpromoter of angiogenesis and lymphangiogenesis [114]

Conflicting results have been published about the trans-forming growth factor-120573 (TGF-120573) Oda et al [115] showedthat homozygous patients for CC genotype from T869Cpolymorphism presented a higher TGF-120573 expression andsuggested a role of this gene as progression marker for breastcarcinoma It is known that overexpression of TGF-120573 by bothtumor and stromal tissue can facilitate the development ofmetastasis mainly in behalf of TGF-120573 stimuli to angiogenesis

and increased tumor cell motility [116] According to Sheen-Chen et al [117] high TGF-1205731 serum levels have beenassociated with advanced stages of breast cancer thus itmay reflect the severity of invasive breast cancer HoweverFigueroa et al [118] found that TGF-120573 expression wascorrelated with favorable prognostic features These resultsare seemingly discordant and possibly represent the dual roleof TGF-120573 in cancer development in which it displays bothtumorigenic and tumor-suppressive effects de Kruijf et al[119] claimed that combining TGF-120573 biomarkers providesprognostic information for patients with stage IndashIII breastcancer The authors believed that this marker could identifypatients at increased risk for disease recurrence that mighttherefore be candidates for additional treatment

46 V-Myc Myelocytomatosis Viral Oncogene Homolog(Avian) (MYC) TheMYC proto-oncogene family (compris-ing c-myc N-myc and L-muc) ranks among the mostexhaustively studied group of genes in biology MYC is abasic helix-loop-helix zipper (bHLHZ) proteinwhose activityis tightly regulated by its direct binding to another bHLHZprotein MAX MYC activation can lead to transcriptionalactivation or repression of specific genes [120] This geneseems to have an important role in carcinogenesis andtumor replication growth metabolism differentiation andapoptosis [121]

Amplification ofMYC has been reported in breast canceras well as in many other cancers However amplification ofthis gene is not established as prognostic or predictive factoryet because there are many inconsistent results [122 123]Notwithstanding several converging studies have suggestedthatMYCmay play an important function in breast cancer

A recent report from Horiuchi et al [124] found thatTNBC tumors exhibit elevated MYC expression resultingin increased activity of the MYC pathway They showedthat CDK inhibition effectively induced tumor regressionindicating that aggressive breast tumors with elevated MYCexpression are uniquely sensitive to CDK inhibitors

MYC amplification shows strong correlation with ERstatus stage of disease (initial) and existence of distantmetastasis and tends to be associated with high histologicgrade positive axillary nodal status and a high S-phasefraction Furthermore its amplification is not significantlyassociated with overall survival of patients with invasivecancer Thus this genetic alteration is a feature of aggressivebreast cancer but is unlikely to be a clinically useful prognos-tic factor [122 125]

Thus despite that the expression of MYC is significantlydifferent between breast cancer patients and healthy controls[126] correlation between MYC amplification and differentclinicopathological parameters are inconsistent Regardlessof lack of evidence for the prognostic significance of MYCamplification it could represent a clinically useful predictiveparameter in metastatic breast cancer [122]

47 Forkhead Box Protein 3 (FOXP3) Forkhead box proteinP3 (Foxp3) plays a critical role in differentiation devel-opment maintenance and function of regulatory T-cells

Disease Markers 7

(Treg) [127] However it does not necessarily confer a Tregphenotype when expressed in CD4+ T lymphocytes HighTreg levels have been reported in peripheral blood lymphnodes and tumor specimens from patients with differenttypes of cancer The precise mechanisms by which Tregssuppress immune cell functions remain unclear and thereare reports of both direct inhibition through cell-cell con-tact and indirect inhibition through the secretion of anti-inflammatory mediators such as interleukin Signals fromthe microenvironment have a profound influence on themaintenance and progression of cancers Although T-cellspresent the most important immunological response intumor growth in the early stages of cancer they becomesuppressive CD4+ and CD8+ regulatory T-cells after chronicstimulation and interactions with tumor cells thus promot-ing rather than inhibiting cancer development and progres-sion [128]

It was recently demonstrated that FOXP3 is expressed atboth mRNA and protein levels in the nucleus of epithelialcells in prostate [129] breast [130 131] and lung [132] It isalready becoming clear that cancer cells can show dysregu-lated FOXP3 expression Several studies have examined thedistribution of FOXP3 in normal and malignant epithelialbreast cells [131 133] Each study has consistently reportedthat FOXP3 is expressed constitutively within the nucleusof healthy epithelial cells However description of FOXP3localization in cancerous epithelia is less definitive Somereports showed a nuclear location similar to that observedin healthy cells whereas others describe either a completeabsence of FOXP3 mutations or a change in subcellulardistribution [129 131 133] When breast cancer survival ratewas correlated with location of this marker patients withFOXP3 restricted to cytoplasm had similarly poor prognosisthan patients with no detectable FOXP3 [131] These datasuggested that failure recruitment of FOXP3 to the nucleuscould act as an important prognostic marker associated witha more aggressive form of breast cancer and poor survivalSimilarly almost 20 of breast cancer cells and 80 of non-malignant cells expressed nuclear FOXP3 when assessingsubcellular distribution of FOXP3 in breast cancer patientsamples [133]

FOXP3 is able to repress the expression ofMYC [129] andin normal breast epithelium is able to bind to and repress theexpression of HER-2 [133] with prognostic relevance [33]

Overbeck-Zubrzycka et al [134] demonstrated that nor-mal breast epithelia expressed FOXP3 constitutively withinnucleus and failed to express CXCR4 whereas breast cancersamples and breast cancer metastasis expressed diminishedlevels of nuclear FOXP3 and also expressed significantlyhigher levels of membrane CXCR4The increased expressionof CXCR4 on these cells allows a potent response to CXCL12and migration to site-specific regions of the body [135 136]

48 microRNA Over the past decades an increasing amountof evidence has demonstrated applications of microRNAs(miRNAs) as tissue based markers for classification andprognosis of several human cancers including breast cancer[137 138]

miRNAs are naturally occurring noncoding small RNAmolecules of 21ndash24 nucleotides that binds partially or com-pletely to 31015840untranslated regions (31015840-UTRs) of protein-codinggenes leading to cleavage or translational repression oftargets [139 140] The miRNA can be stably present in wholeblood serum and plasma [141] but the origin of circulatingmiRNA is still unclear It has been proposed that tumor-associated miRNAs can be released into bloodstream whentumor cells are dying and being lysed [142] or through activesecretion of miRNA loaded exosomes by tumor cells [143]

Some studies have indicated that microRNAs play apivotal role in most critical biological events includingdevelopment proliferation differentiation cell fate determi-nation apoptosis signal transduction organ developmenthematopoietic lineage differentiation host-viral interactionsand tumorigenesis [144 145]

Wu et al [146] detected more than 800 miRNAs in thecirculation of breast cancer patients Two of them miR-375 and miR-122 exhibited strong correlation with clinicaloutcomes including neoadjuvant chemotherapy responseand metastatic relapse These results may allow optimizedchemotherapy treatments and preventive antimetastasisintervention in future clinical applications Wang et al [147]demonstrated that miR-122 acts as a tumor suppressor andplays an important role in inhibiting tumorigenesis throughtargeting IGF1R and regulating PI3KAktmTORp70S6Kpathway

In breast cancer specimens miR-497 expression patternwas negatively correlated with pathological stage lymphaticmetastasis tumor size and HER-2 and no correlation wasfound between miR-497 and ER PR and p53 status Theoverexpression of miR-497 results in downregulation ofBcl-w (antiapoptotic member of the Bcl-2 family) causingcellular growth inhibition and apoptotic enhancement aswell as G0G1 phase arrest acting like a tumor suppressorThus breast cancer patients with elevated expression of miR-497 have better prognosis and this marker may turn out tobe a new prognostic marker [148]

Genome-wide analyses have identified deregulatedmiRNA expression in human malignancies [149] and apotential dual role in tumor formation highlighting thatmiRNAs can modulate oncogenic or tumor suppressorpathways including p53 c-MYC RAS and BCR-ABL whileexpression of miRNAs themselves can be regulated byoncogenes or tumor suppressors

However miRNA can be prejudicial to breast cancerpatient contributing to tumor development For instancemiR-373 and miR-520c stimulate cancer cell migration andinvasion in vitro and in vivo [150] Many studies havedemonstrated the potential of miRNAs as regulators andtheymay serve as novel diagnostic and prognostic candidatesand potential therapeutic targets

5 Conclusion

Breast cancer is the second leading cause of womenmortalityand morbidity worldwide and this cancer represents oneof the most privileged malignancy regarding the use of

8 Disease Markers

markers with predictive values but especially two therapeuticstrategies of great clinical relevance are known and appliedin patient routine Tamoxifen and Trastuzumab Otherwisemanywomen are still diagnosed in advanced stages of diseasewith poor evolution Hence an intense search for markersthat may be crucial in the course of disease especially thosewith prognostic and therapeutic purposes will be needed todevelop personalized treatment In this context some of themolecules discussed in this review provided strong evidencethat evaluation and application of these breast cancermarkerswill play a significant role in more effective and targetedtherapies with lower toxicity to patients

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

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[2] Cancer Genome Atlas Network ldquoComprehensive molecularportraits of human breast tumoursrdquo Nature vol 490 no 7418pp 61ndash70 2012

[3] INCARJ Estimativa 2012 Incidencia de Cancer no Brasil 2011[4] T Vargo-Gogola and JM Rosen ldquoModelling breast cancer one

size does not fit allrdquoNature Reviews Cancer vol 7 no 9 pp 659ndash672 2007

[5] J P Ketterhagen S R Quackenbusch and R A HaushalterldquoTumor histology as a prognostic determinant in carcinoma ofthe breastrdquo Surgery Gynecology andObstetrics vol 158 no 2 pp120ndash123 1984

[6] L Sobin and C Wittekind ldquoTNM classification for esophaguscancerrdquo Hepato-Gastro vol 14 no 6 pp 491ndash492 2007

[7] K Polyak ldquoBreast cancer origins and evolutionrdquo Journal ofClinical Investigation vol 117 no 11 pp 3155ndash3163 2007

[8] L L M Matos N S Leandro M B Maurıcio and M PRoberta ldquoMaria aparecida da silva tecnologia aplicada nadeteccao de marcadores tumoraisrdquo Arquivos Medicos Do ABCvol 30 p 7 2005

[9] F A Pacheco M E M Paschoal and M G C CarvalholdquoMarcadores tumorais no cancer de pulmao um caminho parauma terapia biologicardquo Sociedade Brasileira de Pneumologia eTisiologia vol 28 p 7 2002

[10] A Mishra andM Verma ldquoCancer biomarkers are we ready forthe prime timerdquo Cancers vol 2 no 1 pp 190ndash208 2010

[11] A C Ventura and S D Merajver ldquoGenetic determinants ofaggressive breast cancerrdquo Annual Review of Medicine vol 59pp 199ndash212 2008

[12] C Sotiriou and L Pusztai ldquoGene-expression signatures inbreast cancerrdquo The New England Journal of Medicine vol 360no 8 pp 752ndash800 2009

[13] B Weigelt and J S Reis-Filho ldquoMolecular profiling currentlyoffers no more than tumour morphology and basic immuno-histochemistryrdquo Breast Cancer Research vol 12 no 4 article S52010

[14] E H van Beers and P M Nederlof ldquoArray-CGH and breastcancerrdquo Breast Cancer Research vol 8 no 3 article 210 2006

[15] H Hondermarck A-S Vercoutter-Edouart F Revillion et alldquoProteomics of breast cancer for marker discovery and signalpathway profilingrdquo Proteomics vol 1 no 10 pp 1216ndash1232 2001

[16] M J Piccart-Gebhart ldquoNew developments in hormonereceptor-positive diseaserdquo The oncologist vol 16 pp 40ndash502011

[17] S Z Haslam ldquoThe ontogeny of mousemammary gland respon-siveness to ovarian steroid hormonesrdquo Endocrinology vol 125no 5 pp 2766ndash2772 1989

[18] P P Rosen ldquoAdenomyoepithelioma of the breastrdquo HumanPathology vol 18 no 12 pp 1232ndash1237 1987

[19] M D Althuis J H Fergenbaum M Garcia-Closas L ABrinton M P Madigan and M E Sherman ldquoEtiology ofhormone receptor-defined breast cancer a systematic review ofthe literaturerdquoCancer Epidemiology Biomarkers and Preventionvol 13 no 10 pp 1558ndash1568 2004

[20] K-Y Yoo K Tajima S-K Park et al ldquoPostmenopausal obesityas a breast cancer risk factor according to estrogen and proges-terone receptor status (Japan)rdquoCancer Letters vol 167 no 1 pp57ndash63 2001

[21] J Manjer J Malina G Berglund L Bondeson J P Garne andL Janzon ldquoSmoking associatedwith hormone receptor negativebreast cancerrdquo International Journal of Cancer vol 91 p 5802001

[22] E V Jensen and V C Jordan ldquoThe estrogen receptor a modelfor molecular medicinerdquo Clinical Cancer Research vol 9 no 6pp 1980ndash1989 2003

[23] B Fisher J P Costantino D L Wickerham et al ldquoTamoxifenfor prevention of breast cancer report of the National SurgicalAdjuvant Breast and Bowel Project P-1 Studyrdquo Journal of theNational Cancer Institute vol 90 no 18 pp 1371ndash1388 1998

[24] R J T Cote ldquoCR immunohistochemical detection of steroidhormone receptorsrdquo in Immunomicroscopy A diagnostic ToolFor the surgical pathologist W B Saunders Ed PhiladelphiaPa USA 1994

[25] J M Harvey G M Clark C K Osborne and D C AllredldquoEstrogen receptor status by immunohistochemistry is superiorto the ligand-binding assay for predicting response to adjuvantendocrine therapy in breast cancerrdquo Journal of Clinical Oncol-ogy vol 17 no 5 pp 1474ndash1481 1999

[26] J L Wittliff ldquoSteroid hormone receptors in breast cancerrdquoCancer vol 53 no 3 pp 630ndash643 1984

[27] A L A Eisenberg and S Koifman ldquoCancer de mama mar-cadores tumoraisrdquo Revista Brasileira De Cancerologia vol 47p 11 2001

[28] D J Slamon G M Clark and S G Wong ldquoHuman breastcancer correlation of relapse and survival with amplification ofthe HER-2neu oncogenerdquo Science vol 235 no 4785 pp 177ndash182 1987

[29] D M Barnes ldquoC-erbb-2 amplification in mammary-carcinomardquo Journal of Cellular Biochemistry vol 17 pp132ndash138 1993

[30] T Yamamoto S Ikawa and T Akiyama ldquoSimilarity of proteinencoded by the human c-erb-B-2 gene to epidermal growthfactor receptorrdquo Nature vol 319 no 6050 pp 230ndash234 1986

[31] A Citri K B Skaria and Y Yarden ldquoThe deaf and the dumbthe biology of ErbB-2 and ErbB-3rdquo Experimental Cell Researchvol 284 no 1 pp 54ndash65 2003

[32] F Lonardo E Di Marco C R King et al ldquoThe normal erbB-2 product is an atypical receptor-like tyrosine kinase withconstitutive activity in the absence of ligandrdquoNew Biologist vol2 no 11 pp 992ndash1003 1990

Disease Markers 9

[33] D J Slamon B Leyland-Jones S Shak et al ldquoUse of chemother-apy plus a monoclonal antibody against her2 for metastaticbreast cancer that overexpresses HER2rdquo The New EnglandJournal of Medicine vol 344 no 11 pp 783ndash792 2001

[34] M A Molina J Codony-Servat J Albanell F Rojo J Arribasand J Baselga ldquoTrastuzumab (Herceptin) a humanized anti-HER2 receptor monoclonal antibody inhibits basal and acti-vated HER2 ectodomain cleavage in breast cancer cellsrdquo CancerResearch vol 61 no 12 pp 4744ndash4749 2001

[35] C A Hudis ldquoTrastuzumabmdashmechanism of action and use inclinical practicerdquoTheNew England Journal of Medicine vol 357no 1 pp 39ndash51 2007

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[37] T Narita H Funahashi Y Satoh and H Takagi ldquoC-erbB-2protein in the sera of breast cancer patientsrdquo Breast CancerResearch and Treatment vol 24 no 2 pp 97ndash102 1992

[38] V H C Bramwell G S Doig A B Tuck et al ldquoChangesover time of extracellular domain of HER2 (ECDHER2) serumlevels have prognostic value in metastatic breast cancerrdquo BreastCancer Research andTreatment vol 114 no 3 pp 503ndash511 2009

[39] L-D Tan Y-Y Xu Y Yu X-Q Li Y Chen and Y-MFeng ldquoSerum HER2 level measured by dot blot a valid andinexpensive assay for monitoring breast cancer progressionrdquoPLoS ONE vol 6 no 4 Article ID e18764 2011

[40] R Dent M Trudeau K I Pritchard et al ldquoTriple-negativebreast cancer clinical features and patterns of recurrencerdquoClinical Cancer Research vol 13 no 15 pp 4429ndash4434 2007

[41] K A Cadoo T A Traina and T A King ldquoAdvances inmolecular and clinical subtyping of breast cancer and theirimplications for therapyrdquo Surgical Oncology Clinics of NorthAmerica vol 22 p 823 2013

[42] E Y Cho M H Chang Y L Choi et al ldquoPotential candidatebiomarkers for heterogeneity in triple-negative breast cancer(TNBC)rdquo Cancer Chemotherapy and Pharmacology vol 68 no3 pp 753ndash761 2011

[43] T Soslashrlie R Tibshirani J Parker et al ldquoRepeated observationof breast tumor subtypes in independent gene expression datasetsrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 100 no 14 pp 8418ndash8423 2003

[44] J Gerdes H Lemke and H Baisch ldquoCell cycle analysis of a cellproliferation associated human nuclear antigen defined by themonoclonal antibody Ki-67rdquo Journal of Immunology vol 133no 4 pp 1710ndash1715 1984

[45] F Reyal M A Bollet M Caly et al ldquoRespective prognosticvalue of genomic grade and histological proliferation markersin early stage (pN0) breast carcinomardquo PLoS ONE vol 7 no 4Article ID e35184 2012

[46] P Vielh S Chevillard V Mosseri B Donatini and H Magde-lenat ldquoKi67 index and S-phase fraction in human breast carci-nomas Comparison and correlations with prognostic factorsrdquoAmerican Journal of Clinical Pathology vol 94 no 6 pp 681ndash686 1990

[47] T Soslashrlie Y Wang C Xiao et al ldquoDistinct molecular mecha-nisms underlying clinically relevant subtypes of breast cancergene expression analyses across three different platformsrdquo BMCGenomics vol 7 article 127 2006

[48] A V Patil R Singhai R S Bhamre and V W Patil ldquoKi-67biomarker in breast cancer of Indian womenrdquo North AmericanJournal of Medical Sciences vol 3 no 3 pp 119ndash128 2011

[49] K Tawfik B F Kimler M K Davis F Fan and O TawfikldquoKi-67 expression in axillary lymph node metastases in breastcancer is prognostically significantrdquo Human Pathology vol 44no 1 pp 39ndash46 2013

[50] E Luporsi F Andre F Spyratos et al ldquoKi-67 level of evidenceand methodological considerations for its role in the clinicalmanagement of breast cancer analytical and critical reviewrdquoBreast Cancer Research and Treatment vol 132 no 3 pp 895ndash915 2012

[51] S P Hussain and C C Harris ldquop53 biological network atthe crossroads of the cellular-stress response pathway andmolecular carcinogenesisrdquo Journal of Nippon Medical Schoolvol 73 no 2 pp 54ndash64 2006

[52] T Soslashrlie C M Perou R Tibshirani et al ldquoGene expressionpatterns of breast carcinomas distinguish tumor subclasses withclinical implicationsrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 98 no 19 pp 10869ndash10874 2001

[53] D C Allred G M Clark R Elledge et al ldquoAssociation of p53protein expressionwith tumor cell proliferation rate and clinicaloutcome in node-negative breast cancerrdquo Journal of the NationalCancer Institute vol 85 no 3 pp 200ndash206 1993

[54] A Dumay J P Feugeas E Wittmer J Lehmann-Che PBertheau M Espie et al ldquoDistinct tumor protein p53 mutantsin breast cancer subgroupsrdquo International Journal of Cancer vol132 no 5 pp 1227ndash1231 2013

[55] R M Elledge G M Clark S A W Fuqua Y-Y Yu and DC Allred ldquop53 protein accumulation detected by five differentantibodies relationship to prognosis and heat shock protein 70in breast cancerrdquo Cancer Research vol 54 no 14 pp 3752ndash37571994

[56] M Lacroix ldquoSignificance detection and markers of dissemi-nated breast cancer cellsrdquo Endocrine-Related Cancer vol 13 no4 pp 1033ndash1067 2006

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[60] J AThompson FGrunert andWZimmermann ldquoCarcinoem-bryonic antigen gene family molecular biology and clinicalperspectivesrdquo Journal of Clinical Laboratory Analysis vol 5 no5 pp 344ndash366 1991

[61] R Molina J M Auge B Farrus et al ldquoProspective evaluationof Carcinoembryonic Antigen (CEA) and carbohydrate antigen153 (CA 153) in patients with primary locoregional breastcancerrdquo Clinical Chemistry vol 56 no 7 pp 1148ndash1157 2010

[62] MUehara T Kinoshita THojo S Akashi-Tanaka E Iwamotoand T Fukutomi ldquoLong-term prognostic study of carcinoem-bryonic antigen (CEA) and carbohydrate antigen 15-3 (CA 15-3)in breast cancerrdquo International Journal of Clinical Oncology vol13 no 5 pp 447ndash451 2008

[63] A Thathiah and D D Carson ldquoMT1-MMP mediates MUC1shedding independent of TACEADAM17rdquo Biochemical Jour-nal vol 382 no 1 pp 363ndash373 2004

10 Disease Markers

[64] C L Hattrup and S J Gendler ldquoStructure and function of thecell surface (tethered) mucinsrdquo Annual Review of Physiologyvol 70 pp 431ndash457 2008

[65] M J Duffy S Shering F Sherry E McDermott and NOrsquoHiggins ldquoCA 15-3 a prognostic marker in breast cancerrdquoInternational Journal of Biological Markers vol 15 no 4 pp330ndash333 2000

[66] M T Sandri M Salvatici E Botteri et al ldquoPrognostic roleof CA153 in 7942 patients with operable breast cancerrdquo BreastCancer Research and Treatment vol 132 no 1 pp 317ndash326 2012

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[68] W Jager K Eibner B Loffler S Gleixner and S Kramer ldquoSerialCEA and CA 15-3 measurements during follow-up of breastcancer patientsrdquo Anticancer Research vol 20 no 6 pp 5179ndash5182 2000

[69] P L Welcsh K N Owens and M-C King ldquoInsights into thefunctions of BRCA1 and BRCA2rdquoTrends in Genetics vol 16 no2 pp 69ndash74 2000

[70] A R Venkitaraman ldquoCancer susceptibility and the functions ofBRCA1 and BRCA2rdquo Cell vol 108 no 2 pp 171ndash182 2002

[71] D Bertwistle and A Ashworth ldquoFunctions of the BRCA1 endBRCA2 genesrdquo Current Opinion in Genetics and Developmentvol 8 no 1 pp 14ndash20 1998

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[74] N Senst M Llacuachaqui J Lubinski H Lynch S Armel SNeuhausen et al ldquoParental origin of mutation and the risk ofbreast cancer in a prospective study of women with a BRCA1or BRCA2mutationrdquo Clinical Genetics vol 84 no 1 pp 43ndash462013

[75] N Ikeda Y Miyoshi K Yoneda E Shiba Y Sekihara MKinoshita et al ldquoFrequency of BRCA1 and BRCA2 germlinemutations in Japanese breast cancer familiesrdquo InternationalJournal of Cancer vol 91 no 1 pp 83ndash88 2001

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[77] G F Schwartz K S Hughes H T Lynch et al ldquoProceedingsof the international consensus conference on breast cancer riskgenetics amp risk management April 2007rdquo Cancer vol 113 no10 pp 2627ndash2637 2008

[78] M VanstoneW Chow L Lester P Ainsworth J Nisker andMBrackstone ldquoRecognizingBRCAgenemutation risk subsequentto breast cancer diagnosis in southwestern Ontariordquo CanadianFamily Physician vol 58 no 5 pp E258ndashE266 2012

[79] T R Rebbeck T Friebel H T Lynch et al ldquoBilateral prophylac-ticmastectomy reduces breast cancer risk inBRCA1 and BRCA2mutation carriers the PROSE study grouprdquo Journal of ClinicalOncology vol 22 no 6 pp 1055ndash1062 2004

[80] P Apostolou and F Fostira ldquoHereditary breast cancer the eraof new susceptibility genesrdquo BioMed Research International vol2013 Article ID 747318 2013

[81] G-LMoldovan B Pfander and S Jentsch ldquoPCNA themaestroof the replication forkrdquo Cell vol 129 no 4 pp 665ndash679 2007

[82] R Bravo and H Macdonald-Bravo ldquoExistence of two popula-tions of cyclinproliferating cell nuclear antigen during the cellcycle associationwithDNAreplication sitesrdquoTheJournal of CellBiology vol 105 no 4 pp 1549ndash1554 1987

[83] C W Elston and I O Ellis ldquoPathological prognostic factorsin breast cancer I The value of histological grade in breastcancer experience from a large study with long-term follow-uprdquo Histopathology vol 19 no 5 pp 403ndash410 1991

[84] H Zhao P-C Ho Y-H Lo et al ldquoInteraction of proliferationcell nuclear antigen (PCNA) with c-Abl in cell proliferation andresponse to DNA damages in breast cancerrdquo PLoS ONE vol 7no 1 Article ID e29416 2012

[85] H Zhao Y-H Lo LMa et al ldquoTargeting tyrosine phosphoryla-tion of pcna inhibits prostate cancer growthrdquoMolecular CancerTherapeutics vol 10 no 1 pp 29ndash36 2011

[86] M N Aoki M K Amarante J M M Oda and M A EWatanabe ldquoCaveolin involvement and modulation in breastcancerrdquoMini-Reviews in Medicinal Chemistry vol 11 no 13 pp1143ndash1152 2011

[87] R Hnasko and M P Lisanti ldquoThe biology of caveolae lessonsfrom caveolin knockout mice and implications for humandiseaserdquo Molecular Interventions vol 3 no 8 pp 445ndash4642003

[88] S E Elsheikh A R Green E A Rakha et al ldquoCaveolin 1and caveolin 2 are associated with breast cancer basal-like andtriple-negative immunophenotyperdquo British Journal of Cancervol 99 no 2 pp 327ndash334 2008

[89] J A Karam Y Lotan C G Roehrborn R Ashfaq P IKarakiewicz and S F Shariat ldquoCaveolin-I overexpression isassociated with aggressive prostate cancer recurrencerdquo Prostatevol 67 no 6 pp 614ndash622 2007

[90] C-CHo S-HKuo P-HHuangH-YHuang andC-HYangldquoCaveolin-1 expression is significantly associated with drugresistance and poor prognosis in advanced non-small cell lungcancer patients treated with gemcitabine-based chemotherapyrdquoLung Cancer vol 59 no 1 pp 105ndash110 2008

[91] V Barresi S Cerasoli G Paioli et al ldquoCaveolin-1 in menin-giomas expression and clinico-pathological correlationsrdquo ActaNeuropathologica vol 112 no 5 pp 617ndash626 2006

[92] M Kucia R Reca K Miekus et al ldquoTrafficking of normalstem cells and metastasis of cancer stem cells involve similarmechanisms pivotal role of the SDF-1-CXCR4 axisrdquo Stem Cellsvol 23 no 7 pp 879ndash894 2005

[93] A Muller B Homey H Soto et al ldquoInvolvement of chemokinereceptors in breast cancermetastasisrdquoNature vol 410 no 6824pp 50ndash56 2001

[94] D Mukherjee and J Zhao ldquoThe Role of chemokine receptorCXCR4 in breast cancermetastasisrdquoAmerican Journal of CancerResearch vol 3 no 1 pp 46ndash57 2013

[95] T Schioppa B Uranchimeg A Saccani et al ldquoRegulationof the chemokine receptor CXCR4 by hypoxiardquo Journal ofExperimental Medicine vol 198 no 9 pp 1391ndash1402 2003

[96] H Kang G Watkins C Parr A Douglas-Jones R E Manseland W G Jiang ldquoStromal cell derived factor-1 its influence oninvasiveness and migration of breast cancer cells in vitro andits association with prognosis and survival in human breastcancerrdquo Breast Cancer Research vol 7 no 4 pp R402ndashR4102005

[97] Q D Chu L Panu N T Holm B D L Li L W Johnsonand S Zhang ldquoHigh chemokine receptor CXCR4 level intriple negative breast cancer specimens predicts poor clinical

Disease Markers 11

outcomerdquo Journal of Surgical Research vol 159 no 2 pp 689ndash695 2010

[98] H W Chen C W Du X L Wei U S Khoo and G J ZhangldquoCytoplasmic CXCR4 high-expression exhibits distinct poorclinicopathological characteristics and predicts poor prognosisin triple-negative breast cancerrdquo Current Molecular Medicinevol 13 no 3 pp 410ndash416 2013

[99] J-K Li L Yu Y Shen L-S Zhou Y-C Wang and J-HZhang ldquoInhibition of CXCR4 activity with AMD3100 decreasesinvasion of human colorectal cancer cells in vitrordquo WorldJournal of Gastroenterology vol 14 no 15 pp 2308ndash2313 2008

[100] K Christopherson II and R Hromas ldquoChemokine regulation ofnormal and pathologic immune responsesrdquo Stem Cells vol 19no 5 pp 388ndash396 2001

[101] C R Mackay ldquoChemokines immunologyrsquos high impact fac-torsrdquo Nature Immunology vol 2 no 2 pp 95ndash101 2001

[102] A Zlotnik O Yoshie and H Nomiyama ldquoThe chemokineand chemokine receptor superfamilies and their molecularevolutionrdquo Genome Biology vol 7 no 12 article 243 2006

[103] Y Zhang F Yao X Yao et al ldquoRole of CCL5 in invasionproliferation and proportion of CD44+CD24minus phenotype ofMCF-7 cells and correlation of CCL5 andCCR5 expressionwithbreast cancer progressionrdquo Oncology Reports vol 21 no 4 pp1113ndash1121 2009

[104] W B Fang I Jokar A Zou D Lambert P Dendukuri and NCheng ldquoCCL2CCR2 chemokine signaling coordinates survivaland motility of breast cancer cells through Smad3 protein- andp4244 mitogen-activated protein kinase (MAPK)-dependentmechanismsrdquo The Journal of Biological Chemistry vol 287 pp36593ndash36608 2012

[105] J L Steiner and E A Murphy ldquoImportance of chemokine (CC-motif) ligand 2 in breast cancerrdquo The International Journal ofBiological Markers vol 27 no 3 pp e179ndashe185 2012

[106] X Lu and Y Kang ldquoChemokine (C-C Motif) ligand 2 engagesCCR2+ stromal cells of monocytic origin to promote breastcancer metastasis to lung and bonerdquo The Journal of BiologicalChemistry vol 284 no 42 pp 29087ndash29096 2009

[107] T T Murooka R Rahbar and E N Fish ldquoCCL5 promotesproliferation of MCF-7 cells through mTOR-dependent mRNAtranslationrdquo Biochemical and Biophysical Research Communica-tions vol 387 no 2 pp 381ndash386 2009

[108] M Velasco-Velazquez and R G Pestell ldquoThe CCL5CCR5 axispromotes metastasis in basal breast cancerrdquo Oncoimmunologyvol 2 no 4 Article ID e23660 2013

[109] G Luboshits S Shina O Kaplan et al ldquoElevated expressionof the CC chemokine regulated on activation normal T cellexpressed and secreted (RANTES) in advanced breast carci-nomardquo Cancer Research vol 59 no 18 pp 4681ndash4687 1999

[110] M Cerna A Narsanska V Treska R Kucera and O TopolcanldquoIGF1 and tumor markers in different breast cancer stagesrdquoRozhledy v Chirurgii vol 90 no 12 pp 688ndash694 2011

[111] S Mezi L Todi E Orsi A Angeloni and P Mancini ldquoInvolve-ment of the Src-cortactin pathway inmigration induced by IGF-1 and EGF in human breast cancer cellsrdquo International Journalof Oncology vol 41 no 6 pp 2128ndash2138

[112] R Kucera M Cerna A Narsanska et al ldquoGrowth factorsand breast tumors comparison of selected growth factors withtraditional tumor markersrdquo Anticancer Research vol 31 no 12pp 4653ndash4656 2011

[113] H H Ahmed F MMetwally E S MahdyW G Shosha and SS Ramadan ldquoClinical value of serum hepatocyte growth factor

B-cell lymphoma-2 and nitric oxide in primary breast cancerpatientsrdquo European Review for Medical and PharmacologicalSciences vol 16 p 958 2012

[114] H Arias-Pulido N Chaher Y Gong C Qualls J Vargas andM Royce ldquoTumor stromal vascular endothelial growth factorA is predictive of poor outcome in inflammatory breast cancerrdquoBMC Cancer vol 12 p 298 2012

[115] J MM Oda K B de Oliveira R L Guembarovski KW A deLima A C D D Herrera A L Guembarovski et al ldquoTGF-120573 polymorphism and its expression correlated with CXCR4expression in human breast cancerrdquoMolecular Biology Reportsvol 39 no 12 pp 10131ndash10137 2012

[116] N Dumont and C L Arteaga ldquoTransforming growth factor-120573 and breast cancer tumor promoting effects of transforminggrowth factor-120573rdquo Breast Cancer Research vol 2 no 2 pp 125ndash132 2000

[117] S-M Sheen-Chen H-S Chen C-W Sheen H-L Eng andW-J Chen ldquoSerum levels of transforming growth factor 1205731 inpatients with breast cancerrdquo Archives of Surgery vol 136 no 8pp 937ndash940 2001

[118] J D Figueroa K C Flanders M Garcia-Closas et al ldquoExpres-sion of TGF-120573 signaling factors in invasive breast cancersrelationships with age at diagnosis and tumor characteristicsrdquoBreast Cancer Research and Treatment vol 121 no 3 pp 727ndash735 2010

[119] E M de Kruijf T J Dekker L J Hawinkels H Putter V TSmit J R Kroep et al ldquoThe prognostic role of TGF-120573 signalingpathway in breast cancer patientsrdquo Annals of Oncology vol 24no 2 pp 384ndash390 2013

[120] M Eilers and R N Eisenman ldquoMycrsquos broad reachrdquo Genes andDevelopment vol 22 no 20 pp 2755ndash2766 2008

[121] C V Dang ldquoc-Myc target genes involved in cell growthapoptosis andmetabolismrdquoMolecular and Cellular Biology vol19 no 1 pp 1ndash11 1999

[122] N Todorovic-Rakovic Z Neskovic-Konstantinovic and DNikolic-Vukosavljevic ldquoC-myc as a predictive marker forchemotherapy in metastatic breast cancerrdquo Clinical and Experi-mental Medicine vol 12 no 4 pp 217ndash223 2012

[123] A D Singhi A Cimino-Mathews R B Jenkins et al ldquoMYCgene amplification is often acquired in lethal distant breastcancer metastases of unamplified primary tumorsrdquo ModernPathology vol 25 no 3 pp 378ndash387 2012

[124] D Horiuchi L Kusdra N E Huskey S Chandriani ME Lenburg A M Gonzalez-Angulo et al ldquoMYC pathwayactivation in triple-negative breast cancer is synthetic lethalwith CDK inhibitionrdquo Journal of Experimental Medicine vol209 no 4 pp 679ndash696 2012

[125] J K Rummukainen T Salminen J Lundin S Kytola HJoensuu and J J Isola ldquoAmplification of c-myc by fluorescencein situ hybridization in a population-based breast cancer tissuearrayrdquoModern Pathology vol 14 no 10 pp 1030ndash1035 2001

[126] MOloomi S BouzariMAMohagheghi andHKhodayaran-Tehrani ldquoMolecular markers in peripheral blood of iranianwomen with breast cancerrdquo Cancer Microenviron vol 6 no 1pp 109ndash116 2013

[127] M Sahin E Sahin and S Koksoy ldquoRegulatory T cells in canceran overview and perspectives on cyclooxygenase-2 and Foxp3DNAmethylationrdquoHuman Immunology vol 74 no 9 pp 1061ndash1068 2013

[128] M A E Watanabe J M M Oda M K Amarante and J CesarVoltarelli ldquoRegulatory T cells and breast cancer implications

12 Disease Markers

for immunopathogenesisrdquo Cancer and Metastasis Reviews vol29 no 4 pp 569ndash579 2010

[129] L Wang R Liu W Li et al ldquoSomatic single hits inactivate theX-linked tumor suppressor FOXP3 in the prostaterdquoCancer Cellvol 16 no 4 pp 336ndash346 2009

[130] T Zuo R Liu H Zhang et al ldquoFOXP3 is a novel transcriptionalrepressor for the breast cancer oncogene SKP2rdquo The Journal ofClinical Investigation vol 117 no 12 pp 3765ndash3773 2007

[131] A Balsari A Merlo P Casalini et al ldquoFOXP3 expression andoverall survival in breast cancerrdquo Journal of Clinical Oncologyvol 27 no 11 pp 1746ndash1752 2009

[132] G-Y Chen C Chen L Wang X Chang P Zheng and Y LiuldquoCutting edge broad expression of the FoxP3 locus in epithelialcells a caution against early interpretation of fatal inflammatorydiseases following in vivo depletion of FoxP3-expressing cellsrdquoJournal of Immunology vol 180 no 8 pp 5163ndash5166 2008

[133] T Zuo L Wang C Morrison et al ldquoFOXP3 is an X-linkedbreast cancer suppressor gene and an important repressor ofthe HER-2ErbB2 oncogenerdquo Cell vol 129 no 7 pp 1275ndash12862007

[134] D Overbeck-Zubrzycka S Ali J Kirby and T LennardldquoFOXP3 transcription factor regulates metastatic spread ofbreast cancer via control of expression of CXCR4 chemokinereceptorrdquo British Journal of Surgery vol 98 no 1 pp 84ndash852011

[135] J RHarvey PMellorH Eldaly TW J Lennard J AKirby andS Ali ldquoInhibition of CXCR4-mediated breast cancermetastasisa potential role for heparinoidsrdquo Clinical Cancer Research vol13 no 5 pp 1562ndash1570 2007

[136] P Mellor J R Harvey K J Murphy et al ldquoModulatory effectsof heparin and short-length oligosaccharides of heparin on themetastasis and growth of LMDMDA-MB 231 breast cancer cellsin vivordquo British Journal of Cancer vol 97 no 6 pp 761ndash7682007

[137] M V Iorio M Ferracin C-G Liu et al ldquoMicroRNA geneexpression deregulation in human breast cancerrdquo CancerResearch vol 65 no 16 pp 7065ndash7070 2005

[138] S W Fu L Chen and Y G Man ldquomiRNA biomarkers in breastcancer detection andmanagementrdquo Journal of Cancer vol 2 pp116ndash122 2011

[139] D P Bartel ldquoMicroRNAs genomics biogenesis mechanismand functionrdquo Cell vol 116 no 2 pp 281ndash297 2004

[140] R I Gregory and R Shiekhattar ldquoMicroRNA biogenesis andcancerrdquo Cancer Research vol 65 no 9 pp 3509ndash3512 2005

[141] D D Taylor and C Gercel-Taylor ldquoMicroRNA signatures oftumor-derived exosomes as diagnostic biomarkers of ovariancancerrdquo Gynecologic Oncology vol 110 no 1 pp 13ndash21 2008

[142] L J Chin and F J Slack ldquoA truth serum for cancer microRNAshave major potential as cancer biomarkersrdquo Cell Research vol18 no 10 pp 983ndash984 2008

[143] P S Mitchell R K Parkin E M Kroh et al ldquoCirculatingmicroRNAs as stable blood-based markers for cancer detec-tionrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 105 no 30 pp 10513ndash10518 2008

[144] D P Bartel ldquoMicroRNAs target recognition and regulatoryfunctionsrdquo Cell vol 136 no 2 pp 215ndash233 2009

[145] D J Guarnieri and R J Dileone ldquoMicroRNAs a new class ofgene regulatorsrdquo Annals of Medicine vol 40 no 3 pp 197ndash2082008

[146] XWuG Somlo Y Yu et al ldquoDe novo sequencing of circulatingmiRNAs identifies novel markers predicting clinical outcome

of locally advanced breast cancerrdquo Journal of TranslationalMedicine vol 10 no 1 article 42 2012

[147] B Wang H Wang and Z Yang ldquoMiR-122 inhibits cell prolif-eration and tumorigenesis of breast cancer by targeting IGF1RrdquoPloS ONE vol 7 no 10 Article ID e47053 2012

[148] L Shen J Li L Xu et al ldquomiR-497 induces apoptosis of breastcancer cells by targeting Bcl-wrdquo Experimental and TherapeuticMedicine vol 3 no 3 pp 475ndash480 2012

[149] C M Croce ldquoCauses and consequences of microRNA dysreg-ulation in cancerrdquo Nature Reviews Genetics vol 10 no 10 pp704ndash714 2009

[150] Q Huang K Gumireddy M Schrier et al ldquoThe microRNAsmiR-373 and miR-520c promote tumour invasion and metasta-sisrdquo Nature Cell Biology vol 10 no 2 pp 202ndash210 2008

Submit your manuscripts athttpwwwhindawicom

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Oxidative Medicine and Cellular Longevity

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ObesityJournal of

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MEDIATORSINFLAMMATION

of

6 Disease Markers

likely exerts its protumorigenic effects through recruitmentof tumor-associated macrophages and angiogenesis [105]Furthermore CCL2CCR2 (CCL2 receptor) chemokine sig-naling seems to be implicated in cell migration and itsoverexpression is associated with breast cancer metastasis toboth lung and bone [104 106]

TheCCL5CCR5 (CCL5 receptor) axis is active in patientsaffected by aggressive basal subtype of breast cancerMurookaet al [107] showed that CCL5 enhancedMCF-7 (breast cancercell lines) proliferation Furthermore according to Velasco-Velazquez and Pestell [108] CCR5 promoted breast cancerinvasiveness and metastatic potential These results indi-cated that CCL5 expression is directly correlated with moreadvanced stage of disease emphasizing their involvement inbreast cancer progression [109] In this context these twochemokines could be considered as prognostic markers andtherapeutic targets for breast cancer

45 Growth Factors EGF HGF IGF VEGF and TGF-120573 Therole of growth factors has been extensively analyzed both incancer risk and tumor progression Cerna et al [110] founda negative correlation between insulin-like growth factorI (IGF1) and severity of cancer Thus according to theseauthors this growth factor cannot be used for quick andcorrect orientation in clinical condition of patients in theearly stages of tumor growth unlike epidermal growth factor(EGF) Nevertheless the IGF1 and EGF are stimuli to migra-tion of cancer cells to distant areas to form metastasis andhave been implicated in the development and progression ofhuman breast carcinoma [111]

The hepatocyte growth factor (HGF) is considered aprogression and aggressiveness marker of breast cancer anddata obtained by Kucera et al [112] fully corresponds to thisBased on their data this marker could potentially be usedas an additional tool for the differentiation between benignand malignant tumor Ahmed et al [113] also demonstratedthat serum levels of HGF may help in the diagnosis of breastcancer patients and may aid in disease prognosis HoweverCerna et al [110] related the opposite for HGF as well asIGF1 and vascular endothelial growth factor (VEGF) It wasdemonstrated that tumor stromal VEGF-A expression is avaluable prognostic indicator of breast cancer-specific anddisease-free survival at diagnosis and can therefore be usedto stratify patients with inflammatory breast cancer (IBC)into low-risk and high-risk groups for death and relapsesFurthermore high levels of tumor stromal VEGF-A maybe useful to identify IBC patients who will benefit fromantiangiogenic treatment since VEGF-A is the most potentpromoter of angiogenesis and lymphangiogenesis [114]

Conflicting results have been published about the trans-forming growth factor-120573 (TGF-120573) Oda et al [115] showedthat homozygous patients for CC genotype from T869Cpolymorphism presented a higher TGF-120573 expression andsuggested a role of this gene as progression marker for breastcarcinoma It is known that overexpression of TGF-120573 by bothtumor and stromal tissue can facilitate the development ofmetastasis mainly in behalf of TGF-120573 stimuli to angiogenesis

and increased tumor cell motility [116] According to Sheen-Chen et al [117] high TGF-1205731 serum levels have beenassociated with advanced stages of breast cancer thus itmay reflect the severity of invasive breast cancer HoweverFigueroa et al [118] found that TGF-120573 expression wascorrelated with favorable prognostic features These resultsare seemingly discordant and possibly represent the dual roleof TGF-120573 in cancer development in which it displays bothtumorigenic and tumor-suppressive effects de Kruijf et al[119] claimed that combining TGF-120573 biomarkers providesprognostic information for patients with stage IndashIII breastcancer The authors believed that this marker could identifypatients at increased risk for disease recurrence that mighttherefore be candidates for additional treatment

46 V-Myc Myelocytomatosis Viral Oncogene Homolog(Avian) (MYC) TheMYC proto-oncogene family (compris-ing c-myc N-myc and L-muc) ranks among the mostexhaustively studied group of genes in biology MYC is abasic helix-loop-helix zipper (bHLHZ) proteinwhose activityis tightly regulated by its direct binding to another bHLHZprotein MAX MYC activation can lead to transcriptionalactivation or repression of specific genes [120] This geneseems to have an important role in carcinogenesis andtumor replication growth metabolism differentiation andapoptosis [121]

Amplification ofMYC has been reported in breast canceras well as in many other cancers However amplification ofthis gene is not established as prognostic or predictive factoryet because there are many inconsistent results [122 123]Notwithstanding several converging studies have suggestedthatMYCmay play an important function in breast cancer

A recent report from Horiuchi et al [124] found thatTNBC tumors exhibit elevated MYC expression resultingin increased activity of the MYC pathway They showedthat CDK inhibition effectively induced tumor regressionindicating that aggressive breast tumors with elevated MYCexpression are uniquely sensitive to CDK inhibitors

MYC amplification shows strong correlation with ERstatus stage of disease (initial) and existence of distantmetastasis and tends to be associated with high histologicgrade positive axillary nodal status and a high S-phasefraction Furthermore its amplification is not significantlyassociated with overall survival of patients with invasivecancer Thus this genetic alteration is a feature of aggressivebreast cancer but is unlikely to be a clinically useful prognos-tic factor [122 125]

Thus despite that the expression of MYC is significantlydifferent between breast cancer patients and healthy controls[126] correlation between MYC amplification and differentclinicopathological parameters are inconsistent Regardlessof lack of evidence for the prognostic significance of MYCamplification it could represent a clinically useful predictiveparameter in metastatic breast cancer [122]

47 Forkhead Box Protein 3 (FOXP3) Forkhead box proteinP3 (Foxp3) plays a critical role in differentiation devel-opment maintenance and function of regulatory T-cells

Disease Markers 7

(Treg) [127] However it does not necessarily confer a Tregphenotype when expressed in CD4+ T lymphocytes HighTreg levels have been reported in peripheral blood lymphnodes and tumor specimens from patients with differenttypes of cancer The precise mechanisms by which Tregssuppress immune cell functions remain unclear and thereare reports of both direct inhibition through cell-cell con-tact and indirect inhibition through the secretion of anti-inflammatory mediators such as interleukin Signals fromthe microenvironment have a profound influence on themaintenance and progression of cancers Although T-cellspresent the most important immunological response intumor growth in the early stages of cancer they becomesuppressive CD4+ and CD8+ regulatory T-cells after chronicstimulation and interactions with tumor cells thus promot-ing rather than inhibiting cancer development and progres-sion [128]

It was recently demonstrated that FOXP3 is expressed atboth mRNA and protein levels in the nucleus of epithelialcells in prostate [129] breast [130 131] and lung [132] It isalready becoming clear that cancer cells can show dysregu-lated FOXP3 expression Several studies have examined thedistribution of FOXP3 in normal and malignant epithelialbreast cells [131 133] Each study has consistently reportedthat FOXP3 is expressed constitutively within the nucleusof healthy epithelial cells However description of FOXP3localization in cancerous epithelia is less definitive Somereports showed a nuclear location similar to that observedin healthy cells whereas others describe either a completeabsence of FOXP3 mutations or a change in subcellulardistribution [129 131 133] When breast cancer survival ratewas correlated with location of this marker patients withFOXP3 restricted to cytoplasm had similarly poor prognosisthan patients with no detectable FOXP3 [131] These datasuggested that failure recruitment of FOXP3 to the nucleuscould act as an important prognostic marker associated witha more aggressive form of breast cancer and poor survivalSimilarly almost 20 of breast cancer cells and 80 of non-malignant cells expressed nuclear FOXP3 when assessingsubcellular distribution of FOXP3 in breast cancer patientsamples [133]

FOXP3 is able to repress the expression ofMYC [129] andin normal breast epithelium is able to bind to and repress theexpression of HER-2 [133] with prognostic relevance [33]

Overbeck-Zubrzycka et al [134] demonstrated that nor-mal breast epithelia expressed FOXP3 constitutively withinnucleus and failed to express CXCR4 whereas breast cancersamples and breast cancer metastasis expressed diminishedlevels of nuclear FOXP3 and also expressed significantlyhigher levels of membrane CXCR4The increased expressionof CXCR4 on these cells allows a potent response to CXCL12and migration to site-specific regions of the body [135 136]

48 microRNA Over the past decades an increasing amountof evidence has demonstrated applications of microRNAs(miRNAs) as tissue based markers for classification andprognosis of several human cancers including breast cancer[137 138]

miRNAs are naturally occurring noncoding small RNAmolecules of 21ndash24 nucleotides that binds partially or com-pletely to 31015840untranslated regions (31015840-UTRs) of protein-codinggenes leading to cleavage or translational repression oftargets [139 140] The miRNA can be stably present in wholeblood serum and plasma [141] but the origin of circulatingmiRNA is still unclear It has been proposed that tumor-associated miRNAs can be released into bloodstream whentumor cells are dying and being lysed [142] or through activesecretion of miRNA loaded exosomes by tumor cells [143]

Some studies have indicated that microRNAs play apivotal role in most critical biological events includingdevelopment proliferation differentiation cell fate determi-nation apoptosis signal transduction organ developmenthematopoietic lineage differentiation host-viral interactionsand tumorigenesis [144 145]

Wu et al [146] detected more than 800 miRNAs in thecirculation of breast cancer patients Two of them miR-375 and miR-122 exhibited strong correlation with clinicaloutcomes including neoadjuvant chemotherapy responseand metastatic relapse These results may allow optimizedchemotherapy treatments and preventive antimetastasisintervention in future clinical applications Wang et al [147]demonstrated that miR-122 acts as a tumor suppressor andplays an important role in inhibiting tumorigenesis throughtargeting IGF1R and regulating PI3KAktmTORp70S6Kpathway

In breast cancer specimens miR-497 expression patternwas negatively correlated with pathological stage lymphaticmetastasis tumor size and HER-2 and no correlation wasfound between miR-497 and ER PR and p53 status Theoverexpression of miR-497 results in downregulation ofBcl-w (antiapoptotic member of the Bcl-2 family) causingcellular growth inhibition and apoptotic enhancement aswell as G0G1 phase arrest acting like a tumor suppressorThus breast cancer patients with elevated expression of miR-497 have better prognosis and this marker may turn out tobe a new prognostic marker [148]

Genome-wide analyses have identified deregulatedmiRNA expression in human malignancies [149] and apotential dual role in tumor formation highlighting thatmiRNAs can modulate oncogenic or tumor suppressorpathways including p53 c-MYC RAS and BCR-ABL whileexpression of miRNAs themselves can be regulated byoncogenes or tumor suppressors

However miRNA can be prejudicial to breast cancerpatient contributing to tumor development For instancemiR-373 and miR-520c stimulate cancer cell migration andinvasion in vitro and in vivo [150] Many studies havedemonstrated the potential of miRNAs as regulators andtheymay serve as novel diagnostic and prognostic candidatesand potential therapeutic targets

5 Conclusion

Breast cancer is the second leading cause of womenmortalityand morbidity worldwide and this cancer represents oneof the most privileged malignancy regarding the use of

8 Disease Markers

markers with predictive values but especially two therapeuticstrategies of great clinical relevance are known and appliedin patient routine Tamoxifen and Trastuzumab Otherwisemanywomen are still diagnosed in advanced stages of diseasewith poor evolution Hence an intense search for markersthat may be crucial in the course of disease especially thosewith prognostic and therapeutic purposes will be needed todevelop personalized treatment In this context some of themolecules discussed in this review provided strong evidencethat evaluation and application of these breast cancermarkerswill play a significant role in more effective and targetedtherapies with lower toxicity to patients

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] INCAMS Estimativa 2010 Incidencia de Cancer no Brasil2011

[2] Cancer Genome Atlas Network ldquoComprehensive molecularportraits of human breast tumoursrdquo Nature vol 490 no 7418pp 61ndash70 2012

[3] INCARJ Estimativa 2012 Incidencia de Cancer no Brasil 2011[4] T Vargo-Gogola and JM Rosen ldquoModelling breast cancer one

size does not fit allrdquoNature Reviews Cancer vol 7 no 9 pp 659ndash672 2007

[5] J P Ketterhagen S R Quackenbusch and R A HaushalterldquoTumor histology as a prognostic determinant in carcinoma ofthe breastrdquo Surgery Gynecology andObstetrics vol 158 no 2 pp120ndash123 1984

[6] L Sobin and C Wittekind ldquoTNM classification for esophaguscancerrdquo Hepato-Gastro vol 14 no 6 pp 491ndash492 2007

[7] K Polyak ldquoBreast cancer origins and evolutionrdquo Journal ofClinical Investigation vol 117 no 11 pp 3155ndash3163 2007

[8] L L M Matos N S Leandro M B Maurıcio and M PRoberta ldquoMaria aparecida da silva tecnologia aplicada nadeteccao de marcadores tumoraisrdquo Arquivos Medicos Do ABCvol 30 p 7 2005

[9] F A Pacheco M E M Paschoal and M G C CarvalholdquoMarcadores tumorais no cancer de pulmao um caminho parauma terapia biologicardquo Sociedade Brasileira de Pneumologia eTisiologia vol 28 p 7 2002

[10] A Mishra andM Verma ldquoCancer biomarkers are we ready forthe prime timerdquo Cancers vol 2 no 1 pp 190ndash208 2010

[11] A C Ventura and S D Merajver ldquoGenetic determinants ofaggressive breast cancerrdquo Annual Review of Medicine vol 59pp 199ndash212 2008

[12] C Sotiriou and L Pusztai ldquoGene-expression signatures inbreast cancerrdquo The New England Journal of Medicine vol 360no 8 pp 752ndash800 2009

[13] B Weigelt and J S Reis-Filho ldquoMolecular profiling currentlyoffers no more than tumour morphology and basic immuno-histochemistryrdquo Breast Cancer Research vol 12 no 4 article S52010

[14] E H van Beers and P M Nederlof ldquoArray-CGH and breastcancerrdquo Breast Cancer Research vol 8 no 3 article 210 2006

[15] H Hondermarck A-S Vercoutter-Edouart F Revillion et alldquoProteomics of breast cancer for marker discovery and signalpathway profilingrdquo Proteomics vol 1 no 10 pp 1216ndash1232 2001

[16] M J Piccart-Gebhart ldquoNew developments in hormonereceptor-positive diseaserdquo The oncologist vol 16 pp 40ndash502011

[17] S Z Haslam ldquoThe ontogeny of mousemammary gland respon-siveness to ovarian steroid hormonesrdquo Endocrinology vol 125no 5 pp 2766ndash2772 1989

[18] P P Rosen ldquoAdenomyoepithelioma of the breastrdquo HumanPathology vol 18 no 12 pp 1232ndash1237 1987

[19] M D Althuis J H Fergenbaum M Garcia-Closas L ABrinton M P Madigan and M E Sherman ldquoEtiology ofhormone receptor-defined breast cancer a systematic review ofthe literaturerdquoCancer Epidemiology Biomarkers and Preventionvol 13 no 10 pp 1558ndash1568 2004

[20] K-Y Yoo K Tajima S-K Park et al ldquoPostmenopausal obesityas a breast cancer risk factor according to estrogen and proges-terone receptor status (Japan)rdquoCancer Letters vol 167 no 1 pp57ndash63 2001

[21] J Manjer J Malina G Berglund L Bondeson J P Garne andL Janzon ldquoSmoking associatedwith hormone receptor negativebreast cancerrdquo International Journal of Cancer vol 91 p 5802001

[22] E V Jensen and V C Jordan ldquoThe estrogen receptor a modelfor molecular medicinerdquo Clinical Cancer Research vol 9 no 6pp 1980ndash1989 2003

[23] B Fisher J P Costantino D L Wickerham et al ldquoTamoxifenfor prevention of breast cancer report of the National SurgicalAdjuvant Breast and Bowel Project P-1 Studyrdquo Journal of theNational Cancer Institute vol 90 no 18 pp 1371ndash1388 1998

[24] R J T Cote ldquoCR immunohistochemical detection of steroidhormone receptorsrdquo in Immunomicroscopy A diagnostic ToolFor the surgical pathologist W B Saunders Ed PhiladelphiaPa USA 1994

[25] J M Harvey G M Clark C K Osborne and D C AllredldquoEstrogen receptor status by immunohistochemistry is superiorto the ligand-binding assay for predicting response to adjuvantendocrine therapy in breast cancerrdquo Journal of Clinical Oncol-ogy vol 17 no 5 pp 1474ndash1481 1999

[26] J L Wittliff ldquoSteroid hormone receptors in breast cancerrdquoCancer vol 53 no 3 pp 630ndash643 1984

[27] A L A Eisenberg and S Koifman ldquoCancer de mama mar-cadores tumoraisrdquo Revista Brasileira De Cancerologia vol 47p 11 2001

[28] D J Slamon G M Clark and S G Wong ldquoHuman breastcancer correlation of relapse and survival with amplification ofthe HER-2neu oncogenerdquo Science vol 235 no 4785 pp 177ndash182 1987

[29] D M Barnes ldquoC-erbb-2 amplification in mammary-carcinomardquo Journal of Cellular Biochemistry vol 17 pp132ndash138 1993

[30] T Yamamoto S Ikawa and T Akiyama ldquoSimilarity of proteinencoded by the human c-erb-B-2 gene to epidermal growthfactor receptorrdquo Nature vol 319 no 6050 pp 230ndash234 1986

[31] A Citri K B Skaria and Y Yarden ldquoThe deaf and the dumbthe biology of ErbB-2 and ErbB-3rdquo Experimental Cell Researchvol 284 no 1 pp 54ndash65 2003

[32] F Lonardo E Di Marco C R King et al ldquoThe normal erbB-2 product is an atypical receptor-like tyrosine kinase withconstitutive activity in the absence of ligandrdquoNew Biologist vol2 no 11 pp 992ndash1003 1990

Disease Markers 9

[33] D J Slamon B Leyland-Jones S Shak et al ldquoUse of chemother-apy plus a monoclonal antibody against her2 for metastaticbreast cancer that overexpresses HER2rdquo The New EnglandJournal of Medicine vol 344 no 11 pp 783ndash792 2001

[34] M A Molina J Codony-Servat J Albanell F Rojo J Arribasand J Baselga ldquoTrastuzumab (Herceptin) a humanized anti-HER2 receptor monoclonal antibody inhibits basal and acti-vated HER2 ectodomain cleavage in breast cancer cellsrdquo CancerResearch vol 61 no 12 pp 4744ndash4749 2001

[35] C A Hudis ldquoTrastuzumabmdashmechanism of action and use inclinical practicerdquoTheNew England Journal of Medicine vol 357no 1 pp 39ndash51 2007

[36] S R D Johnston and A Leary ldquoLapatinib a novel EGFRHER2tyrosine kinase inhibitor for cancerrdquoDrugs of Today vol 42 no7 pp 441ndash453 2006

[37] T Narita H Funahashi Y Satoh and H Takagi ldquoC-erbB-2protein in the sera of breast cancer patientsrdquo Breast CancerResearch and Treatment vol 24 no 2 pp 97ndash102 1992

[38] V H C Bramwell G S Doig A B Tuck et al ldquoChangesover time of extracellular domain of HER2 (ECDHER2) serumlevels have prognostic value in metastatic breast cancerrdquo BreastCancer Research andTreatment vol 114 no 3 pp 503ndash511 2009

[39] L-D Tan Y-Y Xu Y Yu X-Q Li Y Chen and Y-MFeng ldquoSerum HER2 level measured by dot blot a valid andinexpensive assay for monitoring breast cancer progressionrdquoPLoS ONE vol 6 no 4 Article ID e18764 2011

[40] R Dent M Trudeau K I Pritchard et al ldquoTriple-negativebreast cancer clinical features and patterns of recurrencerdquoClinical Cancer Research vol 13 no 15 pp 4429ndash4434 2007

[41] K A Cadoo T A Traina and T A King ldquoAdvances inmolecular and clinical subtyping of breast cancer and theirimplications for therapyrdquo Surgical Oncology Clinics of NorthAmerica vol 22 p 823 2013

[42] E Y Cho M H Chang Y L Choi et al ldquoPotential candidatebiomarkers for heterogeneity in triple-negative breast cancer(TNBC)rdquo Cancer Chemotherapy and Pharmacology vol 68 no3 pp 753ndash761 2011

[43] T Soslashrlie R Tibshirani J Parker et al ldquoRepeated observationof breast tumor subtypes in independent gene expression datasetsrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 100 no 14 pp 8418ndash8423 2003

[44] J Gerdes H Lemke and H Baisch ldquoCell cycle analysis of a cellproliferation associated human nuclear antigen defined by themonoclonal antibody Ki-67rdquo Journal of Immunology vol 133no 4 pp 1710ndash1715 1984

[45] F Reyal M A Bollet M Caly et al ldquoRespective prognosticvalue of genomic grade and histological proliferation markersin early stage (pN0) breast carcinomardquo PLoS ONE vol 7 no 4Article ID e35184 2012

[46] P Vielh S Chevillard V Mosseri B Donatini and H Magde-lenat ldquoKi67 index and S-phase fraction in human breast carci-nomas Comparison and correlations with prognostic factorsrdquoAmerican Journal of Clinical Pathology vol 94 no 6 pp 681ndash686 1990

[47] T Soslashrlie Y Wang C Xiao et al ldquoDistinct molecular mecha-nisms underlying clinically relevant subtypes of breast cancergene expression analyses across three different platformsrdquo BMCGenomics vol 7 article 127 2006

[48] A V Patil R Singhai R S Bhamre and V W Patil ldquoKi-67biomarker in breast cancer of Indian womenrdquo North AmericanJournal of Medical Sciences vol 3 no 3 pp 119ndash128 2011

[49] K Tawfik B F Kimler M K Davis F Fan and O TawfikldquoKi-67 expression in axillary lymph node metastases in breastcancer is prognostically significantrdquo Human Pathology vol 44no 1 pp 39ndash46 2013

[50] E Luporsi F Andre F Spyratos et al ldquoKi-67 level of evidenceand methodological considerations for its role in the clinicalmanagement of breast cancer analytical and critical reviewrdquoBreast Cancer Research and Treatment vol 132 no 3 pp 895ndash915 2012

[51] S P Hussain and C C Harris ldquop53 biological network atthe crossroads of the cellular-stress response pathway andmolecular carcinogenesisrdquo Journal of Nippon Medical Schoolvol 73 no 2 pp 54ndash64 2006

[52] T Soslashrlie C M Perou R Tibshirani et al ldquoGene expressionpatterns of breast carcinomas distinguish tumor subclasses withclinical implicationsrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 98 no 19 pp 10869ndash10874 2001

[53] D C Allred G M Clark R Elledge et al ldquoAssociation of p53protein expressionwith tumor cell proliferation rate and clinicaloutcome in node-negative breast cancerrdquo Journal of the NationalCancer Institute vol 85 no 3 pp 200ndash206 1993

[54] A Dumay J P Feugeas E Wittmer J Lehmann-Che PBertheau M Espie et al ldquoDistinct tumor protein p53 mutantsin breast cancer subgroupsrdquo International Journal of Cancer vol132 no 5 pp 1227ndash1231 2013

[55] R M Elledge G M Clark S A W Fuqua Y-Y Yu and DC Allred ldquop53 protein accumulation detected by five differentantibodies relationship to prognosis and heat shock protein 70in breast cancerrdquo Cancer Research vol 54 no 14 pp 3752ndash37571994

[56] M Lacroix ldquoSignificance detection and markers of dissemi-nated breast cancer cellsrdquo Endocrine-Related Cancer vol 13 no4 pp 1033ndash1067 2006

[57] E Vizcarra A Lluch R Cibrian et al ldquoValue of CA 153 inbreast cancer and comparison with CEA and TPA a studyof specificity in disease-free follow-up patients and sensitivityin patients at diagnosis of the first metastasisrdquo Breast CancerResearch and Treatment vol 37 no 3 pp 209ndash216 1996

[58] J G Geraghty E C Coveney F Sherry N J Ohiggins and MJ Duffy ldquoCa-15-3 in patients with locoregional and metastaticbreast-carcinomardquo Cancer vol 70 p 2831 1992

[59] F G Ebeling P StieberMUntch et al ldquoSerumCEAandCA 15-3 as prognostic factors in primary breast cancerrdquo British Journalof Cancer vol 86 no 8 pp 1217ndash1222 2002

[60] J AThompson FGrunert andWZimmermann ldquoCarcinoem-bryonic antigen gene family molecular biology and clinicalperspectivesrdquo Journal of Clinical Laboratory Analysis vol 5 no5 pp 344ndash366 1991

[61] R Molina J M Auge B Farrus et al ldquoProspective evaluationof Carcinoembryonic Antigen (CEA) and carbohydrate antigen153 (CA 153) in patients with primary locoregional breastcancerrdquo Clinical Chemistry vol 56 no 7 pp 1148ndash1157 2010

[62] MUehara T Kinoshita THojo S Akashi-Tanaka E Iwamotoand T Fukutomi ldquoLong-term prognostic study of carcinoem-bryonic antigen (CEA) and carbohydrate antigen 15-3 (CA 15-3)in breast cancerrdquo International Journal of Clinical Oncology vol13 no 5 pp 447ndash451 2008

[63] A Thathiah and D D Carson ldquoMT1-MMP mediates MUC1shedding independent of TACEADAM17rdquo Biochemical Jour-nal vol 382 no 1 pp 363ndash373 2004

10 Disease Markers

[64] C L Hattrup and S J Gendler ldquoStructure and function of thecell surface (tethered) mucinsrdquo Annual Review of Physiologyvol 70 pp 431ndash457 2008

[65] M J Duffy S Shering F Sherry E McDermott and NOrsquoHiggins ldquoCA 15-3 a prognostic marker in breast cancerrdquoInternational Journal of Biological Markers vol 15 no 4 pp330ndash333 2000

[66] M T Sandri M Salvatici E Botteri et al ldquoPrognostic roleof CA153 in 7942 patients with operable breast cancerrdquo BreastCancer Research and Treatment vol 132 no 1 pp 317ndash326 2012

[67] G A Mendes F C R Sturmer and D L Basegio ldquoUtilizacaodosmarcadores CA15 3 e CEAno seguimento de pacientes comneoplasia mamariardquo NewsLab vol 102 p 7 2010

[68] W Jager K Eibner B Loffler S Gleixner and S Kramer ldquoSerialCEA and CA 15-3 measurements during follow-up of breastcancer patientsrdquo Anticancer Research vol 20 no 6 pp 5179ndash5182 2000

[69] P L Welcsh K N Owens and M-C King ldquoInsights into thefunctions of BRCA1 and BRCA2rdquoTrends in Genetics vol 16 no2 pp 69ndash74 2000

[70] A R Venkitaraman ldquoCancer susceptibility and the functions ofBRCA1 and BRCA2rdquo Cell vol 108 no 2 pp 171ndash182 2002

[71] D Bertwistle and A Ashworth ldquoFunctions of the BRCA1 endBRCA2 genesrdquo Current Opinion in Genetics and Developmentvol 8 no 1 pp 14ndash20 1998

[72] N Rahman and M R Stratton ldquoThe genetics of breast cancersusceptibilityrdquo Annual Review of Genetics vol 32 pp 95ndash1211998

[73] I Shapira R J GrallaM Akerman L RWeiselberg V S JohnH Raftopoulos et al Does maternal Or paternal inheritance ofBRCA Mutation Affect the Age of Cancer Diagnosis in MeetingASCOA Texas 2011

[74] N Senst M Llacuachaqui J Lubinski H Lynch S Armel SNeuhausen et al ldquoParental origin of mutation and the risk ofbreast cancer in a prospective study of women with a BRCA1or BRCA2mutationrdquo Clinical Genetics vol 84 no 1 pp 43ndash462013

[75] N Ikeda Y Miyoshi K Yoneda E Shiba Y Sekihara MKinoshita et al ldquoFrequency of BRCA1 and BRCA2 germlinemutations in Japanese breast cancer familiesrdquo InternationalJournal of Cancer vol 91 no 1 pp 83ndash88 2001

[76] M E Robson ldquoTreatment of hereditary breast cancerrdquo Seminarsin Oncology vol 34 no 5 pp 384ndash391 2007

[77] G F Schwartz K S Hughes H T Lynch et al ldquoProceedingsof the international consensus conference on breast cancer riskgenetics amp risk management April 2007rdquo Cancer vol 113 no10 pp 2627ndash2637 2008

[78] M VanstoneW Chow L Lester P Ainsworth J Nisker andMBrackstone ldquoRecognizingBRCAgenemutation risk subsequentto breast cancer diagnosis in southwestern Ontariordquo CanadianFamily Physician vol 58 no 5 pp E258ndashE266 2012

[79] T R Rebbeck T Friebel H T Lynch et al ldquoBilateral prophylac-ticmastectomy reduces breast cancer risk inBRCA1 and BRCA2mutation carriers the PROSE study grouprdquo Journal of ClinicalOncology vol 22 no 6 pp 1055ndash1062 2004

[80] P Apostolou and F Fostira ldquoHereditary breast cancer the eraof new susceptibility genesrdquo BioMed Research International vol2013 Article ID 747318 2013

[81] G-LMoldovan B Pfander and S Jentsch ldquoPCNA themaestroof the replication forkrdquo Cell vol 129 no 4 pp 665ndash679 2007

[82] R Bravo and H Macdonald-Bravo ldquoExistence of two popula-tions of cyclinproliferating cell nuclear antigen during the cellcycle associationwithDNAreplication sitesrdquoTheJournal of CellBiology vol 105 no 4 pp 1549ndash1554 1987

[83] C W Elston and I O Ellis ldquoPathological prognostic factorsin breast cancer I The value of histological grade in breastcancer experience from a large study with long-term follow-uprdquo Histopathology vol 19 no 5 pp 403ndash410 1991

[84] H Zhao P-C Ho Y-H Lo et al ldquoInteraction of proliferationcell nuclear antigen (PCNA) with c-Abl in cell proliferation andresponse to DNA damages in breast cancerrdquo PLoS ONE vol 7no 1 Article ID e29416 2012

[85] H Zhao Y-H Lo LMa et al ldquoTargeting tyrosine phosphoryla-tion of pcna inhibits prostate cancer growthrdquoMolecular CancerTherapeutics vol 10 no 1 pp 29ndash36 2011

[86] M N Aoki M K Amarante J M M Oda and M A EWatanabe ldquoCaveolin involvement and modulation in breastcancerrdquoMini-Reviews in Medicinal Chemistry vol 11 no 13 pp1143ndash1152 2011

[87] R Hnasko and M P Lisanti ldquoThe biology of caveolae lessonsfrom caveolin knockout mice and implications for humandiseaserdquo Molecular Interventions vol 3 no 8 pp 445ndash4642003

[88] S E Elsheikh A R Green E A Rakha et al ldquoCaveolin 1and caveolin 2 are associated with breast cancer basal-like andtriple-negative immunophenotyperdquo British Journal of Cancervol 99 no 2 pp 327ndash334 2008

[89] J A Karam Y Lotan C G Roehrborn R Ashfaq P IKarakiewicz and S F Shariat ldquoCaveolin-I overexpression isassociated with aggressive prostate cancer recurrencerdquo Prostatevol 67 no 6 pp 614ndash622 2007

[90] C-CHo S-HKuo P-HHuangH-YHuang andC-HYangldquoCaveolin-1 expression is significantly associated with drugresistance and poor prognosis in advanced non-small cell lungcancer patients treated with gemcitabine-based chemotherapyrdquoLung Cancer vol 59 no 1 pp 105ndash110 2008

[91] V Barresi S Cerasoli G Paioli et al ldquoCaveolin-1 in menin-giomas expression and clinico-pathological correlationsrdquo ActaNeuropathologica vol 112 no 5 pp 617ndash626 2006

[92] M Kucia R Reca K Miekus et al ldquoTrafficking of normalstem cells and metastasis of cancer stem cells involve similarmechanisms pivotal role of the SDF-1-CXCR4 axisrdquo Stem Cellsvol 23 no 7 pp 879ndash894 2005

[93] A Muller B Homey H Soto et al ldquoInvolvement of chemokinereceptors in breast cancermetastasisrdquoNature vol 410 no 6824pp 50ndash56 2001

[94] D Mukherjee and J Zhao ldquoThe Role of chemokine receptorCXCR4 in breast cancermetastasisrdquoAmerican Journal of CancerResearch vol 3 no 1 pp 46ndash57 2013

[95] T Schioppa B Uranchimeg A Saccani et al ldquoRegulationof the chemokine receptor CXCR4 by hypoxiardquo Journal ofExperimental Medicine vol 198 no 9 pp 1391ndash1402 2003

[96] H Kang G Watkins C Parr A Douglas-Jones R E Manseland W G Jiang ldquoStromal cell derived factor-1 its influence oninvasiveness and migration of breast cancer cells in vitro andits association with prognosis and survival in human breastcancerrdquo Breast Cancer Research vol 7 no 4 pp R402ndashR4102005

[97] Q D Chu L Panu N T Holm B D L Li L W Johnsonand S Zhang ldquoHigh chemokine receptor CXCR4 level intriple negative breast cancer specimens predicts poor clinical

Disease Markers 11

outcomerdquo Journal of Surgical Research vol 159 no 2 pp 689ndash695 2010

[98] H W Chen C W Du X L Wei U S Khoo and G J ZhangldquoCytoplasmic CXCR4 high-expression exhibits distinct poorclinicopathological characteristics and predicts poor prognosisin triple-negative breast cancerrdquo Current Molecular Medicinevol 13 no 3 pp 410ndash416 2013

[99] J-K Li L Yu Y Shen L-S Zhou Y-C Wang and J-HZhang ldquoInhibition of CXCR4 activity with AMD3100 decreasesinvasion of human colorectal cancer cells in vitrordquo WorldJournal of Gastroenterology vol 14 no 15 pp 2308ndash2313 2008

[100] K Christopherson II and R Hromas ldquoChemokine regulation ofnormal and pathologic immune responsesrdquo Stem Cells vol 19no 5 pp 388ndash396 2001

[101] C R Mackay ldquoChemokines immunologyrsquos high impact fac-torsrdquo Nature Immunology vol 2 no 2 pp 95ndash101 2001

[102] A Zlotnik O Yoshie and H Nomiyama ldquoThe chemokineand chemokine receptor superfamilies and their molecularevolutionrdquo Genome Biology vol 7 no 12 article 243 2006

[103] Y Zhang F Yao X Yao et al ldquoRole of CCL5 in invasionproliferation and proportion of CD44+CD24minus phenotype ofMCF-7 cells and correlation of CCL5 andCCR5 expressionwithbreast cancer progressionrdquo Oncology Reports vol 21 no 4 pp1113ndash1121 2009

[104] W B Fang I Jokar A Zou D Lambert P Dendukuri and NCheng ldquoCCL2CCR2 chemokine signaling coordinates survivaland motility of breast cancer cells through Smad3 protein- andp4244 mitogen-activated protein kinase (MAPK)-dependentmechanismsrdquo The Journal of Biological Chemistry vol 287 pp36593ndash36608 2012

[105] J L Steiner and E A Murphy ldquoImportance of chemokine (CC-motif) ligand 2 in breast cancerrdquo The International Journal ofBiological Markers vol 27 no 3 pp e179ndashe185 2012

[106] X Lu and Y Kang ldquoChemokine (C-C Motif) ligand 2 engagesCCR2+ stromal cells of monocytic origin to promote breastcancer metastasis to lung and bonerdquo The Journal of BiologicalChemistry vol 284 no 42 pp 29087ndash29096 2009

[107] T T Murooka R Rahbar and E N Fish ldquoCCL5 promotesproliferation of MCF-7 cells through mTOR-dependent mRNAtranslationrdquo Biochemical and Biophysical Research Communica-tions vol 387 no 2 pp 381ndash386 2009

[108] M Velasco-Velazquez and R G Pestell ldquoThe CCL5CCR5 axispromotes metastasis in basal breast cancerrdquo Oncoimmunologyvol 2 no 4 Article ID e23660 2013

[109] G Luboshits S Shina O Kaplan et al ldquoElevated expressionof the CC chemokine regulated on activation normal T cellexpressed and secreted (RANTES) in advanced breast carci-nomardquo Cancer Research vol 59 no 18 pp 4681ndash4687 1999

[110] M Cerna A Narsanska V Treska R Kucera and O TopolcanldquoIGF1 and tumor markers in different breast cancer stagesrdquoRozhledy v Chirurgii vol 90 no 12 pp 688ndash694 2011

[111] S Mezi L Todi E Orsi A Angeloni and P Mancini ldquoInvolve-ment of the Src-cortactin pathway inmigration induced by IGF-1 and EGF in human breast cancer cellsrdquo International Journalof Oncology vol 41 no 6 pp 2128ndash2138

[112] R Kucera M Cerna A Narsanska et al ldquoGrowth factorsand breast tumors comparison of selected growth factors withtraditional tumor markersrdquo Anticancer Research vol 31 no 12pp 4653ndash4656 2011

[113] H H Ahmed F MMetwally E S MahdyW G Shosha and SS Ramadan ldquoClinical value of serum hepatocyte growth factor

B-cell lymphoma-2 and nitric oxide in primary breast cancerpatientsrdquo European Review for Medical and PharmacologicalSciences vol 16 p 958 2012

[114] H Arias-Pulido N Chaher Y Gong C Qualls J Vargas andM Royce ldquoTumor stromal vascular endothelial growth factorA is predictive of poor outcome in inflammatory breast cancerrdquoBMC Cancer vol 12 p 298 2012

[115] J MM Oda K B de Oliveira R L Guembarovski KW A deLima A C D D Herrera A L Guembarovski et al ldquoTGF-120573 polymorphism and its expression correlated with CXCR4expression in human breast cancerrdquoMolecular Biology Reportsvol 39 no 12 pp 10131ndash10137 2012

[116] N Dumont and C L Arteaga ldquoTransforming growth factor-120573 and breast cancer tumor promoting effects of transforminggrowth factor-120573rdquo Breast Cancer Research vol 2 no 2 pp 125ndash132 2000

[117] S-M Sheen-Chen H-S Chen C-W Sheen H-L Eng andW-J Chen ldquoSerum levels of transforming growth factor 1205731 inpatients with breast cancerrdquo Archives of Surgery vol 136 no 8pp 937ndash940 2001

[118] J D Figueroa K C Flanders M Garcia-Closas et al ldquoExpres-sion of TGF-120573 signaling factors in invasive breast cancersrelationships with age at diagnosis and tumor characteristicsrdquoBreast Cancer Research and Treatment vol 121 no 3 pp 727ndash735 2010

[119] E M de Kruijf T J Dekker L J Hawinkels H Putter V TSmit J R Kroep et al ldquoThe prognostic role of TGF-120573 signalingpathway in breast cancer patientsrdquo Annals of Oncology vol 24no 2 pp 384ndash390 2013

[120] M Eilers and R N Eisenman ldquoMycrsquos broad reachrdquo Genes andDevelopment vol 22 no 20 pp 2755ndash2766 2008

[121] C V Dang ldquoc-Myc target genes involved in cell growthapoptosis andmetabolismrdquoMolecular and Cellular Biology vol19 no 1 pp 1ndash11 1999

[122] N Todorovic-Rakovic Z Neskovic-Konstantinovic and DNikolic-Vukosavljevic ldquoC-myc as a predictive marker forchemotherapy in metastatic breast cancerrdquo Clinical and Experi-mental Medicine vol 12 no 4 pp 217ndash223 2012

[123] A D Singhi A Cimino-Mathews R B Jenkins et al ldquoMYCgene amplification is often acquired in lethal distant breastcancer metastases of unamplified primary tumorsrdquo ModernPathology vol 25 no 3 pp 378ndash387 2012

[124] D Horiuchi L Kusdra N E Huskey S Chandriani ME Lenburg A M Gonzalez-Angulo et al ldquoMYC pathwayactivation in triple-negative breast cancer is synthetic lethalwith CDK inhibitionrdquo Journal of Experimental Medicine vol209 no 4 pp 679ndash696 2012

[125] J K Rummukainen T Salminen J Lundin S Kytola HJoensuu and J J Isola ldquoAmplification of c-myc by fluorescencein situ hybridization in a population-based breast cancer tissuearrayrdquoModern Pathology vol 14 no 10 pp 1030ndash1035 2001

[126] MOloomi S BouzariMAMohagheghi andHKhodayaran-Tehrani ldquoMolecular markers in peripheral blood of iranianwomen with breast cancerrdquo Cancer Microenviron vol 6 no 1pp 109ndash116 2013

[127] M Sahin E Sahin and S Koksoy ldquoRegulatory T cells in canceran overview and perspectives on cyclooxygenase-2 and Foxp3DNAmethylationrdquoHuman Immunology vol 74 no 9 pp 1061ndash1068 2013

[128] M A E Watanabe J M M Oda M K Amarante and J CesarVoltarelli ldquoRegulatory T cells and breast cancer implications

12 Disease Markers

for immunopathogenesisrdquo Cancer and Metastasis Reviews vol29 no 4 pp 569ndash579 2010

[129] L Wang R Liu W Li et al ldquoSomatic single hits inactivate theX-linked tumor suppressor FOXP3 in the prostaterdquoCancer Cellvol 16 no 4 pp 336ndash346 2009

[130] T Zuo R Liu H Zhang et al ldquoFOXP3 is a novel transcriptionalrepressor for the breast cancer oncogene SKP2rdquo The Journal ofClinical Investigation vol 117 no 12 pp 3765ndash3773 2007

[131] A Balsari A Merlo P Casalini et al ldquoFOXP3 expression andoverall survival in breast cancerrdquo Journal of Clinical Oncologyvol 27 no 11 pp 1746ndash1752 2009

[132] G-Y Chen C Chen L Wang X Chang P Zheng and Y LiuldquoCutting edge broad expression of the FoxP3 locus in epithelialcells a caution against early interpretation of fatal inflammatorydiseases following in vivo depletion of FoxP3-expressing cellsrdquoJournal of Immunology vol 180 no 8 pp 5163ndash5166 2008

[133] T Zuo L Wang C Morrison et al ldquoFOXP3 is an X-linkedbreast cancer suppressor gene and an important repressor ofthe HER-2ErbB2 oncogenerdquo Cell vol 129 no 7 pp 1275ndash12862007

[134] D Overbeck-Zubrzycka S Ali J Kirby and T LennardldquoFOXP3 transcription factor regulates metastatic spread ofbreast cancer via control of expression of CXCR4 chemokinereceptorrdquo British Journal of Surgery vol 98 no 1 pp 84ndash852011

[135] J RHarvey PMellorH Eldaly TW J Lennard J AKirby andS Ali ldquoInhibition of CXCR4-mediated breast cancermetastasisa potential role for heparinoidsrdquo Clinical Cancer Research vol13 no 5 pp 1562ndash1570 2007

[136] P Mellor J R Harvey K J Murphy et al ldquoModulatory effectsof heparin and short-length oligosaccharides of heparin on themetastasis and growth of LMDMDA-MB 231 breast cancer cellsin vivordquo British Journal of Cancer vol 97 no 6 pp 761ndash7682007

[137] M V Iorio M Ferracin C-G Liu et al ldquoMicroRNA geneexpression deregulation in human breast cancerrdquo CancerResearch vol 65 no 16 pp 7065ndash7070 2005

[138] S W Fu L Chen and Y G Man ldquomiRNA biomarkers in breastcancer detection andmanagementrdquo Journal of Cancer vol 2 pp116ndash122 2011

[139] D P Bartel ldquoMicroRNAs genomics biogenesis mechanismand functionrdquo Cell vol 116 no 2 pp 281ndash297 2004

[140] R I Gregory and R Shiekhattar ldquoMicroRNA biogenesis andcancerrdquo Cancer Research vol 65 no 9 pp 3509ndash3512 2005

[141] D D Taylor and C Gercel-Taylor ldquoMicroRNA signatures oftumor-derived exosomes as diagnostic biomarkers of ovariancancerrdquo Gynecologic Oncology vol 110 no 1 pp 13ndash21 2008

[142] L J Chin and F J Slack ldquoA truth serum for cancer microRNAshave major potential as cancer biomarkersrdquo Cell Research vol18 no 10 pp 983ndash984 2008

[143] P S Mitchell R K Parkin E M Kroh et al ldquoCirculatingmicroRNAs as stable blood-based markers for cancer detec-tionrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 105 no 30 pp 10513ndash10518 2008

[144] D P Bartel ldquoMicroRNAs target recognition and regulatoryfunctionsrdquo Cell vol 136 no 2 pp 215ndash233 2009

[145] D J Guarnieri and R J Dileone ldquoMicroRNAs a new class ofgene regulatorsrdquo Annals of Medicine vol 40 no 3 pp 197ndash2082008

[146] XWuG Somlo Y Yu et al ldquoDe novo sequencing of circulatingmiRNAs identifies novel markers predicting clinical outcome

of locally advanced breast cancerrdquo Journal of TranslationalMedicine vol 10 no 1 article 42 2012

[147] B Wang H Wang and Z Yang ldquoMiR-122 inhibits cell prolif-eration and tumorigenesis of breast cancer by targeting IGF1RrdquoPloS ONE vol 7 no 10 Article ID e47053 2012

[148] L Shen J Li L Xu et al ldquomiR-497 induces apoptosis of breastcancer cells by targeting Bcl-wrdquo Experimental and TherapeuticMedicine vol 3 no 3 pp 475ndash480 2012

[149] C M Croce ldquoCauses and consequences of microRNA dysreg-ulation in cancerrdquo Nature Reviews Genetics vol 10 no 10 pp704ndash714 2009

[150] Q Huang K Gumireddy M Schrier et al ldquoThe microRNAsmiR-373 and miR-520c promote tumour invasion and metasta-sisrdquo Nature Cell Biology vol 10 no 2 pp 202ndash210 2008

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawi Publishing Corporation httpwwwhindawicom Volume 2013

The Scientific World Journal

International Journal of

EndocrinologyHindawi Publishing Corporationhttpwwwhindawicom

Volume 2013

ISRN Anesthesiology

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OncologyJournal of

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PPARRe sea rch

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

OphthalmologyJournal of

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ISRN AIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

BioMed Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

ISRN Addiction

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

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Computational and Mathematical Methods in Medicine

ISRN Allergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Journal of

Diabetes ResearchJournal of

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Evidence-Based Complementary and Alternative Medicine

Volume 2013Hindawi Publishing Corporationhttpwwwhindawicom

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Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

ISRN Biomarkers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

MEDIATORSINFLAMMATION

of

Disease Markers 7

(Treg) [127] However it does not necessarily confer a Tregphenotype when expressed in CD4+ T lymphocytes HighTreg levels have been reported in peripheral blood lymphnodes and tumor specimens from patients with differenttypes of cancer The precise mechanisms by which Tregssuppress immune cell functions remain unclear and thereare reports of both direct inhibition through cell-cell con-tact and indirect inhibition through the secretion of anti-inflammatory mediators such as interleukin Signals fromthe microenvironment have a profound influence on themaintenance and progression of cancers Although T-cellspresent the most important immunological response intumor growth in the early stages of cancer they becomesuppressive CD4+ and CD8+ regulatory T-cells after chronicstimulation and interactions with tumor cells thus promot-ing rather than inhibiting cancer development and progres-sion [128]

It was recently demonstrated that FOXP3 is expressed atboth mRNA and protein levels in the nucleus of epithelialcells in prostate [129] breast [130 131] and lung [132] It isalready becoming clear that cancer cells can show dysregu-lated FOXP3 expression Several studies have examined thedistribution of FOXP3 in normal and malignant epithelialbreast cells [131 133] Each study has consistently reportedthat FOXP3 is expressed constitutively within the nucleusof healthy epithelial cells However description of FOXP3localization in cancerous epithelia is less definitive Somereports showed a nuclear location similar to that observedin healthy cells whereas others describe either a completeabsence of FOXP3 mutations or a change in subcellulardistribution [129 131 133] When breast cancer survival ratewas correlated with location of this marker patients withFOXP3 restricted to cytoplasm had similarly poor prognosisthan patients with no detectable FOXP3 [131] These datasuggested that failure recruitment of FOXP3 to the nucleuscould act as an important prognostic marker associated witha more aggressive form of breast cancer and poor survivalSimilarly almost 20 of breast cancer cells and 80 of non-malignant cells expressed nuclear FOXP3 when assessingsubcellular distribution of FOXP3 in breast cancer patientsamples [133]

FOXP3 is able to repress the expression ofMYC [129] andin normal breast epithelium is able to bind to and repress theexpression of HER-2 [133] with prognostic relevance [33]

Overbeck-Zubrzycka et al [134] demonstrated that nor-mal breast epithelia expressed FOXP3 constitutively withinnucleus and failed to express CXCR4 whereas breast cancersamples and breast cancer metastasis expressed diminishedlevels of nuclear FOXP3 and also expressed significantlyhigher levels of membrane CXCR4The increased expressionof CXCR4 on these cells allows a potent response to CXCL12and migration to site-specific regions of the body [135 136]

48 microRNA Over the past decades an increasing amountof evidence has demonstrated applications of microRNAs(miRNAs) as tissue based markers for classification andprognosis of several human cancers including breast cancer[137 138]

miRNAs are naturally occurring noncoding small RNAmolecules of 21ndash24 nucleotides that binds partially or com-pletely to 31015840untranslated regions (31015840-UTRs) of protein-codinggenes leading to cleavage or translational repression oftargets [139 140] The miRNA can be stably present in wholeblood serum and plasma [141] but the origin of circulatingmiRNA is still unclear It has been proposed that tumor-associated miRNAs can be released into bloodstream whentumor cells are dying and being lysed [142] or through activesecretion of miRNA loaded exosomes by tumor cells [143]

Some studies have indicated that microRNAs play apivotal role in most critical biological events includingdevelopment proliferation differentiation cell fate determi-nation apoptosis signal transduction organ developmenthematopoietic lineage differentiation host-viral interactionsand tumorigenesis [144 145]

Wu et al [146] detected more than 800 miRNAs in thecirculation of breast cancer patients Two of them miR-375 and miR-122 exhibited strong correlation with clinicaloutcomes including neoadjuvant chemotherapy responseand metastatic relapse These results may allow optimizedchemotherapy treatments and preventive antimetastasisintervention in future clinical applications Wang et al [147]demonstrated that miR-122 acts as a tumor suppressor andplays an important role in inhibiting tumorigenesis throughtargeting IGF1R and regulating PI3KAktmTORp70S6Kpathway

In breast cancer specimens miR-497 expression patternwas negatively correlated with pathological stage lymphaticmetastasis tumor size and HER-2 and no correlation wasfound between miR-497 and ER PR and p53 status Theoverexpression of miR-497 results in downregulation ofBcl-w (antiapoptotic member of the Bcl-2 family) causingcellular growth inhibition and apoptotic enhancement aswell as G0G1 phase arrest acting like a tumor suppressorThus breast cancer patients with elevated expression of miR-497 have better prognosis and this marker may turn out tobe a new prognostic marker [148]

Genome-wide analyses have identified deregulatedmiRNA expression in human malignancies [149] and apotential dual role in tumor formation highlighting thatmiRNAs can modulate oncogenic or tumor suppressorpathways including p53 c-MYC RAS and BCR-ABL whileexpression of miRNAs themselves can be regulated byoncogenes or tumor suppressors

However miRNA can be prejudicial to breast cancerpatient contributing to tumor development For instancemiR-373 and miR-520c stimulate cancer cell migration andinvasion in vitro and in vivo [150] Many studies havedemonstrated the potential of miRNAs as regulators andtheymay serve as novel diagnostic and prognostic candidatesand potential therapeutic targets

5 Conclusion

Breast cancer is the second leading cause of womenmortalityand morbidity worldwide and this cancer represents oneof the most privileged malignancy regarding the use of

8 Disease Markers

markers with predictive values but especially two therapeuticstrategies of great clinical relevance are known and appliedin patient routine Tamoxifen and Trastuzumab Otherwisemanywomen are still diagnosed in advanced stages of diseasewith poor evolution Hence an intense search for markersthat may be crucial in the course of disease especially thosewith prognostic and therapeutic purposes will be needed todevelop personalized treatment In this context some of themolecules discussed in this review provided strong evidencethat evaluation and application of these breast cancermarkerswill play a significant role in more effective and targetedtherapies with lower toxicity to patients

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] INCAMS Estimativa 2010 Incidencia de Cancer no Brasil2011

[2] Cancer Genome Atlas Network ldquoComprehensive molecularportraits of human breast tumoursrdquo Nature vol 490 no 7418pp 61ndash70 2012

[3] INCARJ Estimativa 2012 Incidencia de Cancer no Brasil 2011[4] T Vargo-Gogola and JM Rosen ldquoModelling breast cancer one

size does not fit allrdquoNature Reviews Cancer vol 7 no 9 pp 659ndash672 2007

[5] J P Ketterhagen S R Quackenbusch and R A HaushalterldquoTumor histology as a prognostic determinant in carcinoma ofthe breastrdquo Surgery Gynecology andObstetrics vol 158 no 2 pp120ndash123 1984

[6] L Sobin and C Wittekind ldquoTNM classification for esophaguscancerrdquo Hepato-Gastro vol 14 no 6 pp 491ndash492 2007

[7] K Polyak ldquoBreast cancer origins and evolutionrdquo Journal ofClinical Investigation vol 117 no 11 pp 3155ndash3163 2007

[8] L L M Matos N S Leandro M B Maurıcio and M PRoberta ldquoMaria aparecida da silva tecnologia aplicada nadeteccao de marcadores tumoraisrdquo Arquivos Medicos Do ABCvol 30 p 7 2005

[9] F A Pacheco M E M Paschoal and M G C CarvalholdquoMarcadores tumorais no cancer de pulmao um caminho parauma terapia biologicardquo Sociedade Brasileira de Pneumologia eTisiologia vol 28 p 7 2002

[10] A Mishra andM Verma ldquoCancer biomarkers are we ready forthe prime timerdquo Cancers vol 2 no 1 pp 190ndash208 2010

[11] A C Ventura and S D Merajver ldquoGenetic determinants ofaggressive breast cancerrdquo Annual Review of Medicine vol 59pp 199ndash212 2008

[12] C Sotiriou and L Pusztai ldquoGene-expression signatures inbreast cancerrdquo The New England Journal of Medicine vol 360no 8 pp 752ndash800 2009

[13] B Weigelt and J S Reis-Filho ldquoMolecular profiling currentlyoffers no more than tumour morphology and basic immuno-histochemistryrdquo Breast Cancer Research vol 12 no 4 article S52010

[14] E H van Beers and P M Nederlof ldquoArray-CGH and breastcancerrdquo Breast Cancer Research vol 8 no 3 article 210 2006

[15] H Hondermarck A-S Vercoutter-Edouart F Revillion et alldquoProteomics of breast cancer for marker discovery and signalpathway profilingrdquo Proteomics vol 1 no 10 pp 1216ndash1232 2001

[16] M J Piccart-Gebhart ldquoNew developments in hormonereceptor-positive diseaserdquo The oncologist vol 16 pp 40ndash502011

[17] S Z Haslam ldquoThe ontogeny of mousemammary gland respon-siveness to ovarian steroid hormonesrdquo Endocrinology vol 125no 5 pp 2766ndash2772 1989

[18] P P Rosen ldquoAdenomyoepithelioma of the breastrdquo HumanPathology vol 18 no 12 pp 1232ndash1237 1987

[19] M D Althuis J H Fergenbaum M Garcia-Closas L ABrinton M P Madigan and M E Sherman ldquoEtiology ofhormone receptor-defined breast cancer a systematic review ofthe literaturerdquoCancer Epidemiology Biomarkers and Preventionvol 13 no 10 pp 1558ndash1568 2004

[20] K-Y Yoo K Tajima S-K Park et al ldquoPostmenopausal obesityas a breast cancer risk factor according to estrogen and proges-terone receptor status (Japan)rdquoCancer Letters vol 167 no 1 pp57ndash63 2001

[21] J Manjer J Malina G Berglund L Bondeson J P Garne andL Janzon ldquoSmoking associatedwith hormone receptor negativebreast cancerrdquo International Journal of Cancer vol 91 p 5802001

[22] E V Jensen and V C Jordan ldquoThe estrogen receptor a modelfor molecular medicinerdquo Clinical Cancer Research vol 9 no 6pp 1980ndash1989 2003

[23] B Fisher J P Costantino D L Wickerham et al ldquoTamoxifenfor prevention of breast cancer report of the National SurgicalAdjuvant Breast and Bowel Project P-1 Studyrdquo Journal of theNational Cancer Institute vol 90 no 18 pp 1371ndash1388 1998

[24] R J T Cote ldquoCR immunohistochemical detection of steroidhormone receptorsrdquo in Immunomicroscopy A diagnostic ToolFor the surgical pathologist W B Saunders Ed PhiladelphiaPa USA 1994

[25] J M Harvey G M Clark C K Osborne and D C AllredldquoEstrogen receptor status by immunohistochemistry is superiorto the ligand-binding assay for predicting response to adjuvantendocrine therapy in breast cancerrdquo Journal of Clinical Oncol-ogy vol 17 no 5 pp 1474ndash1481 1999

[26] J L Wittliff ldquoSteroid hormone receptors in breast cancerrdquoCancer vol 53 no 3 pp 630ndash643 1984

[27] A L A Eisenberg and S Koifman ldquoCancer de mama mar-cadores tumoraisrdquo Revista Brasileira De Cancerologia vol 47p 11 2001

[28] D J Slamon G M Clark and S G Wong ldquoHuman breastcancer correlation of relapse and survival with amplification ofthe HER-2neu oncogenerdquo Science vol 235 no 4785 pp 177ndash182 1987

[29] D M Barnes ldquoC-erbb-2 amplification in mammary-carcinomardquo Journal of Cellular Biochemistry vol 17 pp132ndash138 1993

[30] T Yamamoto S Ikawa and T Akiyama ldquoSimilarity of proteinencoded by the human c-erb-B-2 gene to epidermal growthfactor receptorrdquo Nature vol 319 no 6050 pp 230ndash234 1986

[31] A Citri K B Skaria and Y Yarden ldquoThe deaf and the dumbthe biology of ErbB-2 and ErbB-3rdquo Experimental Cell Researchvol 284 no 1 pp 54ndash65 2003

[32] F Lonardo E Di Marco C R King et al ldquoThe normal erbB-2 product is an atypical receptor-like tyrosine kinase withconstitutive activity in the absence of ligandrdquoNew Biologist vol2 no 11 pp 992ndash1003 1990

Disease Markers 9

[33] D J Slamon B Leyland-Jones S Shak et al ldquoUse of chemother-apy plus a monoclonal antibody against her2 for metastaticbreast cancer that overexpresses HER2rdquo The New EnglandJournal of Medicine vol 344 no 11 pp 783ndash792 2001

[34] M A Molina J Codony-Servat J Albanell F Rojo J Arribasand J Baselga ldquoTrastuzumab (Herceptin) a humanized anti-HER2 receptor monoclonal antibody inhibits basal and acti-vated HER2 ectodomain cleavage in breast cancer cellsrdquo CancerResearch vol 61 no 12 pp 4744ndash4749 2001

[35] C A Hudis ldquoTrastuzumabmdashmechanism of action and use inclinical practicerdquoTheNew England Journal of Medicine vol 357no 1 pp 39ndash51 2007

[36] S R D Johnston and A Leary ldquoLapatinib a novel EGFRHER2tyrosine kinase inhibitor for cancerrdquoDrugs of Today vol 42 no7 pp 441ndash453 2006

[37] T Narita H Funahashi Y Satoh and H Takagi ldquoC-erbB-2protein in the sera of breast cancer patientsrdquo Breast CancerResearch and Treatment vol 24 no 2 pp 97ndash102 1992

[38] V H C Bramwell G S Doig A B Tuck et al ldquoChangesover time of extracellular domain of HER2 (ECDHER2) serumlevels have prognostic value in metastatic breast cancerrdquo BreastCancer Research andTreatment vol 114 no 3 pp 503ndash511 2009

[39] L-D Tan Y-Y Xu Y Yu X-Q Li Y Chen and Y-MFeng ldquoSerum HER2 level measured by dot blot a valid andinexpensive assay for monitoring breast cancer progressionrdquoPLoS ONE vol 6 no 4 Article ID e18764 2011

[40] R Dent M Trudeau K I Pritchard et al ldquoTriple-negativebreast cancer clinical features and patterns of recurrencerdquoClinical Cancer Research vol 13 no 15 pp 4429ndash4434 2007

[41] K A Cadoo T A Traina and T A King ldquoAdvances inmolecular and clinical subtyping of breast cancer and theirimplications for therapyrdquo Surgical Oncology Clinics of NorthAmerica vol 22 p 823 2013

[42] E Y Cho M H Chang Y L Choi et al ldquoPotential candidatebiomarkers for heterogeneity in triple-negative breast cancer(TNBC)rdquo Cancer Chemotherapy and Pharmacology vol 68 no3 pp 753ndash761 2011

[43] T Soslashrlie R Tibshirani J Parker et al ldquoRepeated observationof breast tumor subtypes in independent gene expression datasetsrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 100 no 14 pp 8418ndash8423 2003

[44] J Gerdes H Lemke and H Baisch ldquoCell cycle analysis of a cellproliferation associated human nuclear antigen defined by themonoclonal antibody Ki-67rdquo Journal of Immunology vol 133no 4 pp 1710ndash1715 1984

[45] F Reyal M A Bollet M Caly et al ldquoRespective prognosticvalue of genomic grade and histological proliferation markersin early stage (pN0) breast carcinomardquo PLoS ONE vol 7 no 4Article ID e35184 2012

[46] P Vielh S Chevillard V Mosseri B Donatini and H Magde-lenat ldquoKi67 index and S-phase fraction in human breast carci-nomas Comparison and correlations with prognostic factorsrdquoAmerican Journal of Clinical Pathology vol 94 no 6 pp 681ndash686 1990

[47] T Soslashrlie Y Wang C Xiao et al ldquoDistinct molecular mecha-nisms underlying clinically relevant subtypes of breast cancergene expression analyses across three different platformsrdquo BMCGenomics vol 7 article 127 2006

[48] A V Patil R Singhai R S Bhamre and V W Patil ldquoKi-67biomarker in breast cancer of Indian womenrdquo North AmericanJournal of Medical Sciences vol 3 no 3 pp 119ndash128 2011

[49] K Tawfik B F Kimler M K Davis F Fan and O TawfikldquoKi-67 expression in axillary lymph node metastases in breastcancer is prognostically significantrdquo Human Pathology vol 44no 1 pp 39ndash46 2013

[50] E Luporsi F Andre F Spyratos et al ldquoKi-67 level of evidenceand methodological considerations for its role in the clinicalmanagement of breast cancer analytical and critical reviewrdquoBreast Cancer Research and Treatment vol 132 no 3 pp 895ndash915 2012

[51] S P Hussain and C C Harris ldquop53 biological network atthe crossroads of the cellular-stress response pathway andmolecular carcinogenesisrdquo Journal of Nippon Medical Schoolvol 73 no 2 pp 54ndash64 2006

[52] T Soslashrlie C M Perou R Tibshirani et al ldquoGene expressionpatterns of breast carcinomas distinguish tumor subclasses withclinical implicationsrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 98 no 19 pp 10869ndash10874 2001

[53] D C Allred G M Clark R Elledge et al ldquoAssociation of p53protein expressionwith tumor cell proliferation rate and clinicaloutcome in node-negative breast cancerrdquo Journal of the NationalCancer Institute vol 85 no 3 pp 200ndash206 1993

[54] A Dumay J P Feugeas E Wittmer J Lehmann-Che PBertheau M Espie et al ldquoDistinct tumor protein p53 mutantsin breast cancer subgroupsrdquo International Journal of Cancer vol132 no 5 pp 1227ndash1231 2013

[55] R M Elledge G M Clark S A W Fuqua Y-Y Yu and DC Allred ldquop53 protein accumulation detected by five differentantibodies relationship to prognosis and heat shock protein 70in breast cancerrdquo Cancer Research vol 54 no 14 pp 3752ndash37571994

[56] M Lacroix ldquoSignificance detection and markers of dissemi-nated breast cancer cellsrdquo Endocrine-Related Cancer vol 13 no4 pp 1033ndash1067 2006

[57] E Vizcarra A Lluch R Cibrian et al ldquoValue of CA 153 inbreast cancer and comparison with CEA and TPA a studyof specificity in disease-free follow-up patients and sensitivityin patients at diagnosis of the first metastasisrdquo Breast CancerResearch and Treatment vol 37 no 3 pp 209ndash216 1996

[58] J G Geraghty E C Coveney F Sherry N J Ohiggins and MJ Duffy ldquoCa-15-3 in patients with locoregional and metastaticbreast-carcinomardquo Cancer vol 70 p 2831 1992

[59] F G Ebeling P StieberMUntch et al ldquoSerumCEAandCA 15-3 as prognostic factors in primary breast cancerrdquo British Journalof Cancer vol 86 no 8 pp 1217ndash1222 2002

[60] J AThompson FGrunert andWZimmermann ldquoCarcinoem-bryonic antigen gene family molecular biology and clinicalperspectivesrdquo Journal of Clinical Laboratory Analysis vol 5 no5 pp 344ndash366 1991

[61] R Molina J M Auge B Farrus et al ldquoProspective evaluationof Carcinoembryonic Antigen (CEA) and carbohydrate antigen153 (CA 153) in patients with primary locoregional breastcancerrdquo Clinical Chemistry vol 56 no 7 pp 1148ndash1157 2010

[62] MUehara T Kinoshita THojo S Akashi-Tanaka E Iwamotoand T Fukutomi ldquoLong-term prognostic study of carcinoem-bryonic antigen (CEA) and carbohydrate antigen 15-3 (CA 15-3)in breast cancerrdquo International Journal of Clinical Oncology vol13 no 5 pp 447ndash451 2008

[63] A Thathiah and D D Carson ldquoMT1-MMP mediates MUC1shedding independent of TACEADAM17rdquo Biochemical Jour-nal vol 382 no 1 pp 363ndash373 2004

10 Disease Markers

[64] C L Hattrup and S J Gendler ldquoStructure and function of thecell surface (tethered) mucinsrdquo Annual Review of Physiologyvol 70 pp 431ndash457 2008

[65] M J Duffy S Shering F Sherry E McDermott and NOrsquoHiggins ldquoCA 15-3 a prognostic marker in breast cancerrdquoInternational Journal of Biological Markers vol 15 no 4 pp330ndash333 2000

[66] M T Sandri M Salvatici E Botteri et al ldquoPrognostic roleof CA153 in 7942 patients with operable breast cancerrdquo BreastCancer Research and Treatment vol 132 no 1 pp 317ndash326 2012

[67] G A Mendes F C R Sturmer and D L Basegio ldquoUtilizacaodosmarcadores CA15 3 e CEAno seguimento de pacientes comneoplasia mamariardquo NewsLab vol 102 p 7 2010

[68] W Jager K Eibner B Loffler S Gleixner and S Kramer ldquoSerialCEA and CA 15-3 measurements during follow-up of breastcancer patientsrdquo Anticancer Research vol 20 no 6 pp 5179ndash5182 2000

[69] P L Welcsh K N Owens and M-C King ldquoInsights into thefunctions of BRCA1 and BRCA2rdquoTrends in Genetics vol 16 no2 pp 69ndash74 2000

[70] A R Venkitaraman ldquoCancer susceptibility and the functions ofBRCA1 and BRCA2rdquo Cell vol 108 no 2 pp 171ndash182 2002

[71] D Bertwistle and A Ashworth ldquoFunctions of the BRCA1 endBRCA2 genesrdquo Current Opinion in Genetics and Developmentvol 8 no 1 pp 14ndash20 1998

[72] N Rahman and M R Stratton ldquoThe genetics of breast cancersusceptibilityrdquo Annual Review of Genetics vol 32 pp 95ndash1211998

[73] I Shapira R J GrallaM Akerman L RWeiselberg V S JohnH Raftopoulos et al Does maternal Or paternal inheritance ofBRCA Mutation Affect the Age of Cancer Diagnosis in MeetingASCOA Texas 2011

[74] N Senst M Llacuachaqui J Lubinski H Lynch S Armel SNeuhausen et al ldquoParental origin of mutation and the risk ofbreast cancer in a prospective study of women with a BRCA1or BRCA2mutationrdquo Clinical Genetics vol 84 no 1 pp 43ndash462013

[75] N Ikeda Y Miyoshi K Yoneda E Shiba Y Sekihara MKinoshita et al ldquoFrequency of BRCA1 and BRCA2 germlinemutations in Japanese breast cancer familiesrdquo InternationalJournal of Cancer vol 91 no 1 pp 83ndash88 2001

[76] M E Robson ldquoTreatment of hereditary breast cancerrdquo Seminarsin Oncology vol 34 no 5 pp 384ndash391 2007

[77] G F Schwartz K S Hughes H T Lynch et al ldquoProceedingsof the international consensus conference on breast cancer riskgenetics amp risk management April 2007rdquo Cancer vol 113 no10 pp 2627ndash2637 2008

[78] M VanstoneW Chow L Lester P Ainsworth J Nisker andMBrackstone ldquoRecognizingBRCAgenemutation risk subsequentto breast cancer diagnosis in southwestern Ontariordquo CanadianFamily Physician vol 58 no 5 pp E258ndashE266 2012

[79] T R Rebbeck T Friebel H T Lynch et al ldquoBilateral prophylac-ticmastectomy reduces breast cancer risk inBRCA1 and BRCA2mutation carriers the PROSE study grouprdquo Journal of ClinicalOncology vol 22 no 6 pp 1055ndash1062 2004

[80] P Apostolou and F Fostira ldquoHereditary breast cancer the eraof new susceptibility genesrdquo BioMed Research International vol2013 Article ID 747318 2013

[81] G-LMoldovan B Pfander and S Jentsch ldquoPCNA themaestroof the replication forkrdquo Cell vol 129 no 4 pp 665ndash679 2007

[82] R Bravo and H Macdonald-Bravo ldquoExistence of two popula-tions of cyclinproliferating cell nuclear antigen during the cellcycle associationwithDNAreplication sitesrdquoTheJournal of CellBiology vol 105 no 4 pp 1549ndash1554 1987

[83] C W Elston and I O Ellis ldquoPathological prognostic factorsin breast cancer I The value of histological grade in breastcancer experience from a large study with long-term follow-uprdquo Histopathology vol 19 no 5 pp 403ndash410 1991

[84] H Zhao P-C Ho Y-H Lo et al ldquoInteraction of proliferationcell nuclear antigen (PCNA) with c-Abl in cell proliferation andresponse to DNA damages in breast cancerrdquo PLoS ONE vol 7no 1 Article ID e29416 2012

[85] H Zhao Y-H Lo LMa et al ldquoTargeting tyrosine phosphoryla-tion of pcna inhibits prostate cancer growthrdquoMolecular CancerTherapeutics vol 10 no 1 pp 29ndash36 2011

[86] M N Aoki M K Amarante J M M Oda and M A EWatanabe ldquoCaveolin involvement and modulation in breastcancerrdquoMini-Reviews in Medicinal Chemistry vol 11 no 13 pp1143ndash1152 2011

[87] R Hnasko and M P Lisanti ldquoThe biology of caveolae lessonsfrom caveolin knockout mice and implications for humandiseaserdquo Molecular Interventions vol 3 no 8 pp 445ndash4642003

[88] S E Elsheikh A R Green E A Rakha et al ldquoCaveolin 1and caveolin 2 are associated with breast cancer basal-like andtriple-negative immunophenotyperdquo British Journal of Cancervol 99 no 2 pp 327ndash334 2008

[89] J A Karam Y Lotan C G Roehrborn R Ashfaq P IKarakiewicz and S F Shariat ldquoCaveolin-I overexpression isassociated with aggressive prostate cancer recurrencerdquo Prostatevol 67 no 6 pp 614ndash622 2007

[90] C-CHo S-HKuo P-HHuangH-YHuang andC-HYangldquoCaveolin-1 expression is significantly associated with drugresistance and poor prognosis in advanced non-small cell lungcancer patients treated with gemcitabine-based chemotherapyrdquoLung Cancer vol 59 no 1 pp 105ndash110 2008

[91] V Barresi S Cerasoli G Paioli et al ldquoCaveolin-1 in menin-giomas expression and clinico-pathological correlationsrdquo ActaNeuropathologica vol 112 no 5 pp 617ndash626 2006

[92] M Kucia R Reca K Miekus et al ldquoTrafficking of normalstem cells and metastasis of cancer stem cells involve similarmechanisms pivotal role of the SDF-1-CXCR4 axisrdquo Stem Cellsvol 23 no 7 pp 879ndash894 2005

[93] A Muller B Homey H Soto et al ldquoInvolvement of chemokinereceptors in breast cancermetastasisrdquoNature vol 410 no 6824pp 50ndash56 2001

[94] D Mukherjee and J Zhao ldquoThe Role of chemokine receptorCXCR4 in breast cancermetastasisrdquoAmerican Journal of CancerResearch vol 3 no 1 pp 46ndash57 2013

[95] T Schioppa B Uranchimeg A Saccani et al ldquoRegulationof the chemokine receptor CXCR4 by hypoxiardquo Journal ofExperimental Medicine vol 198 no 9 pp 1391ndash1402 2003

[96] H Kang G Watkins C Parr A Douglas-Jones R E Manseland W G Jiang ldquoStromal cell derived factor-1 its influence oninvasiveness and migration of breast cancer cells in vitro andits association with prognosis and survival in human breastcancerrdquo Breast Cancer Research vol 7 no 4 pp R402ndashR4102005

[97] Q D Chu L Panu N T Holm B D L Li L W Johnsonand S Zhang ldquoHigh chemokine receptor CXCR4 level intriple negative breast cancer specimens predicts poor clinical

Disease Markers 11

outcomerdquo Journal of Surgical Research vol 159 no 2 pp 689ndash695 2010

[98] H W Chen C W Du X L Wei U S Khoo and G J ZhangldquoCytoplasmic CXCR4 high-expression exhibits distinct poorclinicopathological characteristics and predicts poor prognosisin triple-negative breast cancerrdquo Current Molecular Medicinevol 13 no 3 pp 410ndash416 2013

[99] J-K Li L Yu Y Shen L-S Zhou Y-C Wang and J-HZhang ldquoInhibition of CXCR4 activity with AMD3100 decreasesinvasion of human colorectal cancer cells in vitrordquo WorldJournal of Gastroenterology vol 14 no 15 pp 2308ndash2313 2008

[100] K Christopherson II and R Hromas ldquoChemokine regulation ofnormal and pathologic immune responsesrdquo Stem Cells vol 19no 5 pp 388ndash396 2001

[101] C R Mackay ldquoChemokines immunologyrsquos high impact fac-torsrdquo Nature Immunology vol 2 no 2 pp 95ndash101 2001

[102] A Zlotnik O Yoshie and H Nomiyama ldquoThe chemokineand chemokine receptor superfamilies and their molecularevolutionrdquo Genome Biology vol 7 no 12 article 243 2006

[103] Y Zhang F Yao X Yao et al ldquoRole of CCL5 in invasionproliferation and proportion of CD44+CD24minus phenotype ofMCF-7 cells and correlation of CCL5 andCCR5 expressionwithbreast cancer progressionrdquo Oncology Reports vol 21 no 4 pp1113ndash1121 2009

[104] W B Fang I Jokar A Zou D Lambert P Dendukuri and NCheng ldquoCCL2CCR2 chemokine signaling coordinates survivaland motility of breast cancer cells through Smad3 protein- andp4244 mitogen-activated protein kinase (MAPK)-dependentmechanismsrdquo The Journal of Biological Chemistry vol 287 pp36593ndash36608 2012

[105] J L Steiner and E A Murphy ldquoImportance of chemokine (CC-motif) ligand 2 in breast cancerrdquo The International Journal ofBiological Markers vol 27 no 3 pp e179ndashe185 2012

[106] X Lu and Y Kang ldquoChemokine (C-C Motif) ligand 2 engagesCCR2+ stromal cells of monocytic origin to promote breastcancer metastasis to lung and bonerdquo The Journal of BiologicalChemistry vol 284 no 42 pp 29087ndash29096 2009

[107] T T Murooka R Rahbar and E N Fish ldquoCCL5 promotesproliferation of MCF-7 cells through mTOR-dependent mRNAtranslationrdquo Biochemical and Biophysical Research Communica-tions vol 387 no 2 pp 381ndash386 2009

[108] M Velasco-Velazquez and R G Pestell ldquoThe CCL5CCR5 axispromotes metastasis in basal breast cancerrdquo Oncoimmunologyvol 2 no 4 Article ID e23660 2013

[109] G Luboshits S Shina O Kaplan et al ldquoElevated expressionof the CC chemokine regulated on activation normal T cellexpressed and secreted (RANTES) in advanced breast carci-nomardquo Cancer Research vol 59 no 18 pp 4681ndash4687 1999

[110] M Cerna A Narsanska V Treska R Kucera and O TopolcanldquoIGF1 and tumor markers in different breast cancer stagesrdquoRozhledy v Chirurgii vol 90 no 12 pp 688ndash694 2011

[111] S Mezi L Todi E Orsi A Angeloni and P Mancini ldquoInvolve-ment of the Src-cortactin pathway inmigration induced by IGF-1 and EGF in human breast cancer cellsrdquo International Journalof Oncology vol 41 no 6 pp 2128ndash2138

[112] R Kucera M Cerna A Narsanska et al ldquoGrowth factorsand breast tumors comparison of selected growth factors withtraditional tumor markersrdquo Anticancer Research vol 31 no 12pp 4653ndash4656 2011

[113] H H Ahmed F MMetwally E S MahdyW G Shosha and SS Ramadan ldquoClinical value of serum hepatocyte growth factor

B-cell lymphoma-2 and nitric oxide in primary breast cancerpatientsrdquo European Review for Medical and PharmacologicalSciences vol 16 p 958 2012

[114] H Arias-Pulido N Chaher Y Gong C Qualls J Vargas andM Royce ldquoTumor stromal vascular endothelial growth factorA is predictive of poor outcome in inflammatory breast cancerrdquoBMC Cancer vol 12 p 298 2012

[115] J MM Oda K B de Oliveira R L Guembarovski KW A deLima A C D D Herrera A L Guembarovski et al ldquoTGF-120573 polymorphism and its expression correlated with CXCR4expression in human breast cancerrdquoMolecular Biology Reportsvol 39 no 12 pp 10131ndash10137 2012

[116] N Dumont and C L Arteaga ldquoTransforming growth factor-120573 and breast cancer tumor promoting effects of transforminggrowth factor-120573rdquo Breast Cancer Research vol 2 no 2 pp 125ndash132 2000

[117] S-M Sheen-Chen H-S Chen C-W Sheen H-L Eng andW-J Chen ldquoSerum levels of transforming growth factor 1205731 inpatients with breast cancerrdquo Archives of Surgery vol 136 no 8pp 937ndash940 2001

[118] J D Figueroa K C Flanders M Garcia-Closas et al ldquoExpres-sion of TGF-120573 signaling factors in invasive breast cancersrelationships with age at diagnosis and tumor characteristicsrdquoBreast Cancer Research and Treatment vol 121 no 3 pp 727ndash735 2010

[119] E M de Kruijf T J Dekker L J Hawinkels H Putter V TSmit J R Kroep et al ldquoThe prognostic role of TGF-120573 signalingpathway in breast cancer patientsrdquo Annals of Oncology vol 24no 2 pp 384ndash390 2013

[120] M Eilers and R N Eisenman ldquoMycrsquos broad reachrdquo Genes andDevelopment vol 22 no 20 pp 2755ndash2766 2008

[121] C V Dang ldquoc-Myc target genes involved in cell growthapoptosis andmetabolismrdquoMolecular and Cellular Biology vol19 no 1 pp 1ndash11 1999

[122] N Todorovic-Rakovic Z Neskovic-Konstantinovic and DNikolic-Vukosavljevic ldquoC-myc as a predictive marker forchemotherapy in metastatic breast cancerrdquo Clinical and Experi-mental Medicine vol 12 no 4 pp 217ndash223 2012

[123] A D Singhi A Cimino-Mathews R B Jenkins et al ldquoMYCgene amplification is often acquired in lethal distant breastcancer metastases of unamplified primary tumorsrdquo ModernPathology vol 25 no 3 pp 378ndash387 2012

[124] D Horiuchi L Kusdra N E Huskey S Chandriani ME Lenburg A M Gonzalez-Angulo et al ldquoMYC pathwayactivation in triple-negative breast cancer is synthetic lethalwith CDK inhibitionrdquo Journal of Experimental Medicine vol209 no 4 pp 679ndash696 2012

[125] J K Rummukainen T Salminen J Lundin S Kytola HJoensuu and J J Isola ldquoAmplification of c-myc by fluorescencein situ hybridization in a population-based breast cancer tissuearrayrdquoModern Pathology vol 14 no 10 pp 1030ndash1035 2001

[126] MOloomi S BouzariMAMohagheghi andHKhodayaran-Tehrani ldquoMolecular markers in peripheral blood of iranianwomen with breast cancerrdquo Cancer Microenviron vol 6 no 1pp 109ndash116 2013

[127] M Sahin E Sahin and S Koksoy ldquoRegulatory T cells in canceran overview and perspectives on cyclooxygenase-2 and Foxp3DNAmethylationrdquoHuman Immunology vol 74 no 9 pp 1061ndash1068 2013

[128] M A E Watanabe J M M Oda M K Amarante and J CesarVoltarelli ldquoRegulatory T cells and breast cancer implications

12 Disease Markers

for immunopathogenesisrdquo Cancer and Metastasis Reviews vol29 no 4 pp 569ndash579 2010

[129] L Wang R Liu W Li et al ldquoSomatic single hits inactivate theX-linked tumor suppressor FOXP3 in the prostaterdquoCancer Cellvol 16 no 4 pp 336ndash346 2009

[130] T Zuo R Liu H Zhang et al ldquoFOXP3 is a novel transcriptionalrepressor for the breast cancer oncogene SKP2rdquo The Journal ofClinical Investigation vol 117 no 12 pp 3765ndash3773 2007

[131] A Balsari A Merlo P Casalini et al ldquoFOXP3 expression andoverall survival in breast cancerrdquo Journal of Clinical Oncologyvol 27 no 11 pp 1746ndash1752 2009

[132] G-Y Chen C Chen L Wang X Chang P Zheng and Y LiuldquoCutting edge broad expression of the FoxP3 locus in epithelialcells a caution against early interpretation of fatal inflammatorydiseases following in vivo depletion of FoxP3-expressing cellsrdquoJournal of Immunology vol 180 no 8 pp 5163ndash5166 2008

[133] T Zuo L Wang C Morrison et al ldquoFOXP3 is an X-linkedbreast cancer suppressor gene and an important repressor ofthe HER-2ErbB2 oncogenerdquo Cell vol 129 no 7 pp 1275ndash12862007

[134] D Overbeck-Zubrzycka S Ali J Kirby and T LennardldquoFOXP3 transcription factor regulates metastatic spread ofbreast cancer via control of expression of CXCR4 chemokinereceptorrdquo British Journal of Surgery vol 98 no 1 pp 84ndash852011

[135] J RHarvey PMellorH Eldaly TW J Lennard J AKirby andS Ali ldquoInhibition of CXCR4-mediated breast cancermetastasisa potential role for heparinoidsrdquo Clinical Cancer Research vol13 no 5 pp 1562ndash1570 2007

[136] P Mellor J R Harvey K J Murphy et al ldquoModulatory effectsof heparin and short-length oligosaccharides of heparin on themetastasis and growth of LMDMDA-MB 231 breast cancer cellsin vivordquo British Journal of Cancer vol 97 no 6 pp 761ndash7682007

[137] M V Iorio M Ferracin C-G Liu et al ldquoMicroRNA geneexpression deregulation in human breast cancerrdquo CancerResearch vol 65 no 16 pp 7065ndash7070 2005

[138] S W Fu L Chen and Y G Man ldquomiRNA biomarkers in breastcancer detection andmanagementrdquo Journal of Cancer vol 2 pp116ndash122 2011

[139] D P Bartel ldquoMicroRNAs genomics biogenesis mechanismand functionrdquo Cell vol 116 no 2 pp 281ndash297 2004

[140] R I Gregory and R Shiekhattar ldquoMicroRNA biogenesis andcancerrdquo Cancer Research vol 65 no 9 pp 3509ndash3512 2005

[141] D D Taylor and C Gercel-Taylor ldquoMicroRNA signatures oftumor-derived exosomes as diagnostic biomarkers of ovariancancerrdquo Gynecologic Oncology vol 110 no 1 pp 13ndash21 2008

[142] L J Chin and F J Slack ldquoA truth serum for cancer microRNAshave major potential as cancer biomarkersrdquo Cell Research vol18 no 10 pp 983ndash984 2008

[143] P S Mitchell R K Parkin E M Kroh et al ldquoCirculatingmicroRNAs as stable blood-based markers for cancer detec-tionrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 105 no 30 pp 10513ndash10518 2008

[144] D P Bartel ldquoMicroRNAs target recognition and regulatoryfunctionsrdquo Cell vol 136 no 2 pp 215ndash233 2009

[145] D J Guarnieri and R J Dileone ldquoMicroRNAs a new class ofgene regulatorsrdquo Annals of Medicine vol 40 no 3 pp 197ndash2082008

[146] XWuG Somlo Y Yu et al ldquoDe novo sequencing of circulatingmiRNAs identifies novel markers predicting clinical outcome

of locally advanced breast cancerrdquo Journal of TranslationalMedicine vol 10 no 1 article 42 2012

[147] B Wang H Wang and Z Yang ldquoMiR-122 inhibits cell prolif-eration and tumorigenesis of breast cancer by targeting IGF1RrdquoPloS ONE vol 7 no 10 Article ID e47053 2012

[148] L Shen J Li L Xu et al ldquomiR-497 induces apoptosis of breastcancer cells by targeting Bcl-wrdquo Experimental and TherapeuticMedicine vol 3 no 3 pp 475ndash480 2012

[149] C M Croce ldquoCauses and consequences of microRNA dysreg-ulation in cancerrdquo Nature Reviews Genetics vol 10 no 10 pp704ndash714 2009

[150] Q Huang K Gumireddy M Schrier et al ldquoThe microRNAsmiR-373 and miR-520c promote tumour invasion and metasta-sisrdquo Nature Cell Biology vol 10 no 2 pp 202ndash210 2008

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawi Publishing Corporation httpwwwhindawicom Volume 2013

The Scientific World Journal

International Journal of

EndocrinologyHindawi Publishing Corporationhttpwwwhindawicom

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ISRN Anesthesiology

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OncologyJournal of

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PPARRe sea rch

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OphthalmologyJournal of

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BioMed Research International

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ObesityJournal of

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ISRN Addiction

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

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Computational and Mathematical Methods in Medicine

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Journal of

Diabetes ResearchJournal of

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Evidence-Based Complementary and Alternative Medicine

Volume 2013Hindawi Publishing Corporationhttpwwwhindawicom

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Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

ISRN Biomarkers

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MEDIATORSINFLAMMATION

of

8 Disease Markers

markers with predictive values but especially two therapeuticstrategies of great clinical relevance are known and appliedin patient routine Tamoxifen and Trastuzumab Otherwisemanywomen are still diagnosed in advanced stages of diseasewith poor evolution Hence an intense search for markersthat may be crucial in the course of disease especially thosewith prognostic and therapeutic purposes will be needed todevelop personalized treatment In this context some of themolecules discussed in this review provided strong evidencethat evaluation and application of these breast cancermarkerswill play a significant role in more effective and targetedtherapies with lower toxicity to patients

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] INCAMS Estimativa 2010 Incidencia de Cancer no Brasil2011

[2] Cancer Genome Atlas Network ldquoComprehensive molecularportraits of human breast tumoursrdquo Nature vol 490 no 7418pp 61ndash70 2012

[3] INCARJ Estimativa 2012 Incidencia de Cancer no Brasil 2011[4] T Vargo-Gogola and JM Rosen ldquoModelling breast cancer one

size does not fit allrdquoNature Reviews Cancer vol 7 no 9 pp 659ndash672 2007

[5] J P Ketterhagen S R Quackenbusch and R A HaushalterldquoTumor histology as a prognostic determinant in carcinoma ofthe breastrdquo Surgery Gynecology andObstetrics vol 158 no 2 pp120ndash123 1984

[6] L Sobin and C Wittekind ldquoTNM classification for esophaguscancerrdquo Hepato-Gastro vol 14 no 6 pp 491ndash492 2007

[7] K Polyak ldquoBreast cancer origins and evolutionrdquo Journal ofClinical Investigation vol 117 no 11 pp 3155ndash3163 2007

[8] L L M Matos N S Leandro M B Maurıcio and M PRoberta ldquoMaria aparecida da silva tecnologia aplicada nadeteccao de marcadores tumoraisrdquo Arquivos Medicos Do ABCvol 30 p 7 2005

[9] F A Pacheco M E M Paschoal and M G C CarvalholdquoMarcadores tumorais no cancer de pulmao um caminho parauma terapia biologicardquo Sociedade Brasileira de Pneumologia eTisiologia vol 28 p 7 2002

[10] A Mishra andM Verma ldquoCancer biomarkers are we ready forthe prime timerdquo Cancers vol 2 no 1 pp 190ndash208 2010

[11] A C Ventura and S D Merajver ldquoGenetic determinants ofaggressive breast cancerrdquo Annual Review of Medicine vol 59pp 199ndash212 2008

[12] C Sotiriou and L Pusztai ldquoGene-expression signatures inbreast cancerrdquo The New England Journal of Medicine vol 360no 8 pp 752ndash800 2009

[13] B Weigelt and J S Reis-Filho ldquoMolecular profiling currentlyoffers no more than tumour morphology and basic immuno-histochemistryrdquo Breast Cancer Research vol 12 no 4 article S52010

[14] E H van Beers and P M Nederlof ldquoArray-CGH and breastcancerrdquo Breast Cancer Research vol 8 no 3 article 210 2006

[15] H Hondermarck A-S Vercoutter-Edouart F Revillion et alldquoProteomics of breast cancer for marker discovery and signalpathway profilingrdquo Proteomics vol 1 no 10 pp 1216ndash1232 2001

[16] M J Piccart-Gebhart ldquoNew developments in hormonereceptor-positive diseaserdquo The oncologist vol 16 pp 40ndash502011

[17] S Z Haslam ldquoThe ontogeny of mousemammary gland respon-siveness to ovarian steroid hormonesrdquo Endocrinology vol 125no 5 pp 2766ndash2772 1989

[18] P P Rosen ldquoAdenomyoepithelioma of the breastrdquo HumanPathology vol 18 no 12 pp 1232ndash1237 1987

[19] M D Althuis J H Fergenbaum M Garcia-Closas L ABrinton M P Madigan and M E Sherman ldquoEtiology ofhormone receptor-defined breast cancer a systematic review ofthe literaturerdquoCancer Epidemiology Biomarkers and Preventionvol 13 no 10 pp 1558ndash1568 2004

[20] K-Y Yoo K Tajima S-K Park et al ldquoPostmenopausal obesityas a breast cancer risk factor according to estrogen and proges-terone receptor status (Japan)rdquoCancer Letters vol 167 no 1 pp57ndash63 2001

[21] J Manjer J Malina G Berglund L Bondeson J P Garne andL Janzon ldquoSmoking associatedwith hormone receptor negativebreast cancerrdquo International Journal of Cancer vol 91 p 5802001

[22] E V Jensen and V C Jordan ldquoThe estrogen receptor a modelfor molecular medicinerdquo Clinical Cancer Research vol 9 no 6pp 1980ndash1989 2003

[23] B Fisher J P Costantino D L Wickerham et al ldquoTamoxifenfor prevention of breast cancer report of the National SurgicalAdjuvant Breast and Bowel Project P-1 Studyrdquo Journal of theNational Cancer Institute vol 90 no 18 pp 1371ndash1388 1998

[24] R J T Cote ldquoCR immunohistochemical detection of steroidhormone receptorsrdquo in Immunomicroscopy A diagnostic ToolFor the surgical pathologist W B Saunders Ed PhiladelphiaPa USA 1994

[25] J M Harvey G M Clark C K Osborne and D C AllredldquoEstrogen receptor status by immunohistochemistry is superiorto the ligand-binding assay for predicting response to adjuvantendocrine therapy in breast cancerrdquo Journal of Clinical Oncol-ogy vol 17 no 5 pp 1474ndash1481 1999

[26] J L Wittliff ldquoSteroid hormone receptors in breast cancerrdquoCancer vol 53 no 3 pp 630ndash643 1984

[27] A L A Eisenberg and S Koifman ldquoCancer de mama mar-cadores tumoraisrdquo Revista Brasileira De Cancerologia vol 47p 11 2001

[28] D J Slamon G M Clark and S G Wong ldquoHuman breastcancer correlation of relapse and survival with amplification ofthe HER-2neu oncogenerdquo Science vol 235 no 4785 pp 177ndash182 1987

[29] D M Barnes ldquoC-erbb-2 amplification in mammary-carcinomardquo Journal of Cellular Biochemistry vol 17 pp132ndash138 1993

[30] T Yamamoto S Ikawa and T Akiyama ldquoSimilarity of proteinencoded by the human c-erb-B-2 gene to epidermal growthfactor receptorrdquo Nature vol 319 no 6050 pp 230ndash234 1986

[31] A Citri K B Skaria and Y Yarden ldquoThe deaf and the dumbthe biology of ErbB-2 and ErbB-3rdquo Experimental Cell Researchvol 284 no 1 pp 54ndash65 2003

[32] F Lonardo E Di Marco C R King et al ldquoThe normal erbB-2 product is an atypical receptor-like tyrosine kinase withconstitutive activity in the absence of ligandrdquoNew Biologist vol2 no 11 pp 992ndash1003 1990

Disease Markers 9

[33] D J Slamon B Leyland-Jones S Shak et al ldquoUse of chemother-apy plus a monoclonal antibody against her2 for metastaticbreast cancer that overexpresses HER2rdquo The New EnglandJournal of Medicine vol 344 no 11 pp 783ndash792 2001

[34] M A Molina J Codony-Servat J Albanell F Rojo J Arribasand J Baselga ldquoTrastuzumab (Herceptin) a humanized anti-HER2 receptor monoclonal antibody inhibits basal and acti-vated HER2 ectodomain cleavage in breast cancer cellsrdquo CancerResearch vol 61 no 12 pp 4744ndash4749 2001

[35] C A Hudis ldquoTrastuzumabmdashmechanism of action and use inclinical practicerdquoTheNew England Journal of Medicine vol 357no 1 pp 39ndash51 2007

[36] S R D Johnston and A Leary ldquoLapatinib a novel EGFRHER2tyrosine kinase inhibitor for cancerrdquoDrugs of Today vol 42 no7 pp 441ndash453 2006

[37] T Narita H Funahashi Y Satoh and H Takagi ldquoC-erbB-2protein in the sera of breast cancer patientsrdquo Breast CancerResearch and Treatment vol 24 no 2 pp 97ndash102 1992

[38] V H C Bramwell G S Doig A B Tuck et al ldquoChangesover time of extracellular domain of HER2 (ECDHER2) serumlevels have prognostic value in metastatic breast cancerrdquo BreastCancer Research andTreatment vol 114 no 3 pp 503ndash511 2009

[39] L-D Tan Y-Y Xu Y Yu X-Q Li Y Chen and Y-MFeng ldquoSerum HER2 level measured by dot blot a valid andinexpensive assay for monitoring breast cancer progressionrdquoPLoS ONE vol 6 no 4 Article ID e18764 2011

[40] R Dent M Trudeau K I Pritchard et al ldquoTriple-negativebreast cancer clinical features and patterns of recurrencerdquoClinical Cancer Research vol 13 no 15 pp 4429ndash4434 2007

[41] K A Cadoo T A Traina and T A King ldquoAdvances inmolecular and clinical subtyping of breast cancer and theirimplications for therapyrdquo Surgical Oncology Clinics of NorthAmerica vol 22 p 823 2013

[42] E Y Cho M H Chang Y L Choi et al ldquoPotential candidatebiomarkers for heterogeneity in triple-negative breast cancer(TNBC)rdquo Cancer Chemotherapy and Pharmacology vol 68 no3 pp 753ndash761 2011

[43] T Soslashrlie R Tibshirani J Parker et al ldquoRepeated observationof breast tumor subtypes in independent gene expression datasetsrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 100 no 14 pp 8418ndash8423 2003

[44] J Gerdes H Lemke and H Baisch ldquoCell cycle analysis of a cellproliferation associated human nuclear antigen defined by themonoclonal antibody Ki-67rdquo Journal of Immunology vol 133no 4 pp 1710ndash1715 1984

[45] F Reyal M A Bollet M Caly et al ldquoRespective prognosticvalue of genomic grade and histological proliferation markersin early stage (pN0) breast carcinomardquo PLoS ONE vol 7 no 4Article ID e35184 2012

[46] P Vielh S Chevillard V Mosseri B Donatini and H Magde-lenat ldquoKi67 index and S-phase fraction in human breast carci-nomas Comparison and correlations with prognostic factorsrdquoAmerican Journal of Clinical Pathology vol 94 no 6 pp 681ndash686 1990

[47] T Soslashrlie Y Wang C Xiao et al ldquoDistinct molecular mecha-nisms underlying clinically relevant subtypes of breast cancergene expression analyses across three different platformsrdquo BMCGenomics vol 7 article 127 2006

[48] A V Patil R Singhai R S Bhamre and V W Patil ldquoKi-67biomarker in breast cancer of Indian womenrdquo North AmericanJournal of Medical Sciences vol 3 no 3 pp 119ndash128 2011

[49] K Tawfik B F Kimler M K Davis F Fan and O TawfikldquoKi-67 expression in axillary lymph node metastases in breastcancer is prognostically significantrdquo Human Pathology vol 44no 1 pp 39ndash46 2013

[50] E Luporsi F Andre F Spyratos et al ldquoKi-67 level of evidenceand methodological considerations for its role in the clinicalmanagement of breast cancer analytical and critical reviewrdquoBreast Cancer Research and Treatment vol 132 no 3 pp 895ndash915 2012

[51] S P Hussain and C C Harris ldquop53 biological network atthe crossroads of the cellular-stress response pathway andmolecular carcinogenesisrdquo Journal of Nippon Medical Schoolvol 73 no 2 pp 54ndash64 2006

[52] T Soslashrlie C M Perou R Tibshirani et al ldquoGene expressionpatterns of breast carcinomas distinguish tumor subclasses withclinical implicationsrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 98 no 19 pp 10869ndash10874 2001

[53] D C Allred G M Clark R Elledge et al ldquoAssociation of p53protein expressionwith tumor cell proliferation rate and clinicaloutcome in node-negative breast cancerrdquo Journal of the NationalCancer Institute vol 85 no 3 pp 200ndash206 1993

[54] A Dumay J P Feugeas E Wittmer J Lehmann-Che PBertheau M Espie et al ldquoDistinct tumor protein p53 mutantsin breast cancer subgroupsrdquo International Journal of Cancer vol132 no 5 pp 1227ndash1231 2013

[55] R M Elledge G M Clark S A W Fuqua Y-Y Yu and DC Allred ldquop53 protein accumulation detected by five differentantibodies relationship to prognosis and heat shock protein 70in breast cancerrdquo Cancer Research vol 54 no 14 pp 3752ndash37571994

[56] M Lacroix ldquoSignificance detection and markers of dissemi-nated breast cancer cellsrdquo Endocrine-Related Cancer vol 13 no4 pp 1033ndash1067 2006

[57] E Vizcarra A Lluch R Cibrian et al ldquoValue of CA 153 inbreast cancer and comparison with CEA and TPA a studyof specificity in disease-free follow-up patients and sensitivityin patients at diagnosis of the first metastasisrdquo Breast CancerResearch and Treatment vol 37 no 3 pp 209ndash216 1996

[58] J G Geraghty E C Coveney F Sherry N J Ohiggins and MJ Duffy ldquoCa-15-3 in patients with locoregional and metastaticbreast-carcinomardquo Cancer vol 70 p 2831 1992

[59] F G Ebeling P StieberMUntch et al ldquoSerumCEAandCA 15-3 as prognostic factors in primary breast cancerrdquo British Journalof Cancer vol 86 no 8 pp 1217ndash1222 2002

[60] J AThompson FGrunert andWZimmermann ldquoCarcinoem-bryonic antigen gene family molecular biology and clinicalperspectivesrdquo Journal of Clinical Laboratory Analysis vol 5 no5 pp 344ndash366 1991

[61] R Molina J M Auge B Farrus et al ldquoProspective evaluationof Carcinoembryonic Antigen (CEA) and carbohydrate antigen153 (CA 153) in patients with primary locoregional breastcancerrdquo Clinical Chemistry vol 56 no 7 pp 1148ndash1157 2010

[62] MUehara T Kinoshita THojo S Akashi-Tanaka E Iwamotoand T Fukutomi ldquoLong-term prognostic study of carcinoem-bryonic antigen (CEA) and carbohydrate antigen 15-3 (CA 15-3)in breast cancerrdquo International Journal of Clinical Oncology vol13 no 5 pp 447ndash451 2008

[63] A Thathiah and D D Carson ldquoMT1-MMP mediates MUC1shedding independent of TACEADAM17rdquo Biochemical Jour-nal vol 382 no 1 pp 363ndash373 2004

10 Disease Markers

[64] C L Hattrup and S J Gendler ldquoStructure and function of thecell surface (tethered) mucinsrdquo Annual Review of Physiologyvol 70 pp 431ndash457 2008

[65] M J Duffy S Shering F Sherry E McDermott and NOrsquoHiggins ldquoCA 15-3 a prognostic marker in breast cancerrdquoInternational Journal of Biological Markers vol 15 no 4 pp330ndash333 2000

[66] M T Sandri M Salvatici E Botteri et al ldquoPrognostic roleof CA153 in 7942 patients with operable breast cancerrdquo BreastCancer Research and Treatment vol 132 no 1 pp 317ndash326 2012

[67] G A Mendes F C R Sturmer and D L Basegio ldquoUtilizacaodosmarcadores CA15 3 e CEAno seguimento de pacientes comneoplasia mamariardquo NewsLab vol 102 p 7 2010

[68] W Jager K Eibner B Loffler S Gleixner and S Kramer ldquoSerialCEA and CA 15-3 measurements during follow-up of breastcancer patientsrdquo Anticancer Research vol 20 no 6 pp 5179ndash5182 2000

[69] P L Welcsh K N Owens and M-C King ldquoInsights into thefunctions of BRCA1 and BRCA2rdquoTrends in Genetics vol 16 no2 pp 69ndash74 2000

[70] A R Venkitaraman ldquoCancer susceptibility and the functions ofBRCA1 and BRCA2rdquo Cell vol 108 no 2 pp 171ndash182 2002

[71] D Bertwistle and A Ashworth ldquoFunctions of the BRCA1 endBRCA2 genesrdquo Current Opinion in Genetics and Developmentvol 8 no 1 pp 14ndash20 1998

[72] N Rahman and M R Stratton ldquoThe genetics of breast cancersusceptibilityrdquo Annual Review of Genetics vol 32 pp 95ndash1211998

[73] I Shapira R J GrallaM Akerman L RWeiselberg V S JohnH Raftopoulos et al Does maternal Or paternal inheritance ofBRCA Mutation Affect the Age of Cancer Diagnosis in MeetingASCOA Texas 2011

[74] N Senst M Llacuachaqui J Lubinski H Lynch S Armel SNeuhausen et al ldquoParental origin of mutation and the risk ofbreast cancer in a prospective study of women with a BRCA1or BRCA2mutationrdquo Clinical Genetics vol 84 no 1 pp 43ndash462013

[75] N Ikeda Y Miyoshi K Yoneda E Shiba Y Sekihara MKinoshita et al ldquoFrequency of BRCA1 and BRCA2 germlinemutations in Japanese breast cancer familiesrdquo InternationalJournal of Cancer vol 91 no 1 pp 83ndash88 2001

[76] M E Robson ldquoTreatment of hereditary breast cancerrdquo Seminarsin Oncology vol 34 no 5 pp 384ndash391 2007

[77] G F Schwartz K S Hughes H T Lynch et al ldquoProceedingsof the international consensus conference on breast cancer riskgenetics amp risk management April 2007rdquo Cancer vol 113 no10 pp 2627ndash2637 2008

[78] M VanstoneW Chow L Lester P Ainsworth J Nisker andMBrackstone ldquoRecognizingBRCAgenemutation risk subsequentto breast cancer diagnosis in southwestern Ontariordquo CanadianFamily Physician vol 58 no 5 pp E258ndashE266 2012

[79] T R Rebbeck T Friebel H T Lynch et al ldquoBilateral prophylac-ticmastectomy reduces breast cancer risk inBRCA1 and BRCA2mutation carriers the PROSE study grouprdquo Journal of ClinicalOncology vol 22 no 6 pp 1055ndash1062 2004

[80] P Apostolou and F Fostira ldquoHereditary breast cancer the eraof new susceptibility genesrdquo BioMed Research International vol2013 Article ID 747318 2013

[81] G-LMoldovan B Pfander and S Jentsch ldquoPCNA themaestroof the replication forkrdquo Cell vol 129 no 4 pp 665ndash679 2007

[82] R Bravo and H Macdonald-Bravo ldquoExistence of two popula-tions of cyclinproliferating cell nuclear antigen during the cellcycle associationwithDNAreplication sitesrdquoTheJournal of CellBiology vol 105 no 4 pp 1549ndash1554 1987

[83] C W Elston and I O Ellis ldquoPathological prognostic factorsin breast cancer I The value of histological grade in breastcancer experience from a large study with long-term follow-uprdquo Histopathology vol 19 no 5 pp 403ndash410 1991

[84] H Zhao P-C Ho Y-H Lo et al ldquoInteraction of proliferationcell nuclear antigen (PCNA) with c-Abl in cell proliferation andresponse to DNA damages in breast cancerrdquo PLoS ONE vol 7no 1 Article ID e29416 2012

[85] H Zhao Y-H Lo LMa et al ldquoTargeting tyrosine phosphoryla-tion of pcna inhibits prostate cancer growthrdquoMolecular CancerTherapeutics vol 10 no 1 pp 29ndash36 2011

[86] M N Aoki M K Amarante J M M Oda and M A EWatanabe ldquoCaveolin involvement and modulation in breastcancerrdquoMini-Reviews in Medicinal Chemistry vol 11 no 13 pp1143ndash1152 2011

[87] R Hnasko and M P Lisanti ldquoThe biology of caveolae lessonsfrom caveolin knockout mice and implications for humandiseaserdquo Molecular Interventions vol 3 no 8 pp 445ndash4642003

[88] S E Elsheikh A R Green E A Rakha et al ldquoCaveolin 1and caveolin 2 are associated with breast cancer basal-like andtriple-negative immunophenotyperdquo British Journal of Cancervol 99 no 2 pp 327ndash334 2008

[89] J A Karam Y Lotan C G Roehrborn R Ashfaq P IKarakiewicz and S F Shariat ldquoCaveolin-I overexpression isassociated with aggressive prostate cancer recurrencerdquo Prostatevol 67 no 6 pp 614ndash622 2007

[90] C-CHo S-HKuo P-HHuangH-YHuang andC-HYangldquoCaveolin-1 expression is significantly associated with drugresistance and poor prognosis in advanced non-small cell lungcancer patients treated with gemcitabine-based chemotherapyrdquoLung Cancer vol 59 no 1 pp 105ndash110 2008

[91] V Barresi S Cerasoli G Paioli et al ldquoCaveolin-1 in menin-giomas expression and clinico-pathological correlationsrdquo ActaNeuropathologica vol 112 no 5 pp 617ndash626 2006

[92] M Kucia R Reca K Miekus et al ldquoTrafficking of normalstem cells and metastasis of cancer stem cells involve similarmechanisms pivotal role of the SDF-1-CXCR4 axisrdquo Stem Cellsvol 23 no 7 pp 879ndash894 2005

[93] A Muller B Homey H Soto et al ldquoInvolvement of chemokinereceptors in breast cancermetastasisrdquoNature vol 410 no 6824pp 50ndash56 2001

[94] D Mukherjee and J Zhao ldquoThe Role of chemokine receptorCXCR4 in breast cancermetastasisrdquoAmerican Journal of CancerResearch vol 3 no 1 pp 46ndash57 2013

[95] T Schioppa B Uranchimeg A Saccani et al ldquoRegulationof the chemokine receptor CXCR4 by hypoxiardquo Journal ofExperimental Medicine vol 198 no 9 pp 1391ndash1402 2003

[96] H Kang G Watkins C Parr A Douglas-Jones R E Manseland W G Jiang ldquoStromal cell derived factor-1 its influence oninvasiveness and migration of breast cancer cells in vitro andits association with prognosis and survival in human breastcancerrdquo Breast Cancer Research vol 7 no 4 pp R402ndashR4102005

[97] Q D Chu L Panu N T Holm B D L Li L W Johnsonand S Zhang ldquoHigh chemokine receptor CXCR4 level intriple negative breast cancer specimens predicts poor clinical

Disease Markers 11

outcomerdquo Journal of Surgical Research vol 159 no 2 pp 689ndash695 2010

[98] H W Chen C W Du X L Wei U S Khoo and G J ZhangldquoCytoplasmic CXCR4 high-expression exhibits distinct poorclinicopathological characteristics and predicts poor prognosisin triple-negative breast cancerrdquo Current Molecular Medicinevol 13 no 3 pp 410ndash416 2013

[99] J-K Li L Yu Y Shen L-S Zhou Y-C Wang and J-HZhang ldquoInhibition of CXCR4 activity with AMD3100 decreasesinvasion of human colorectal cancer cells in vitrordquo WorldJournal of Gastroenterology vol 14 no 15 pp 2308ndash2313 2008

[100] K Christopherson II and R Hromas ldquoChemokine regulation ofnormal and pathologic immune responsesrdquo Stem Cells vol 19no 5 pp 388ndash396 2001

[101] C R Mackay ldquoChemokines immunologyrsquos high impact fac-torsrdquo Nature Immunology vol 2 no 2 pp 95ndash101 2001

[102] A Zlotnik O Yoshie and H Nomiyama ldquoThe chemokineand chemokine receptor superfamilies and their molecularevolutionrdquo Genome Biology vol 7 no 12 article 243 2006

[103] Y Zhang F Yao X Yao et al ldquoRole of CCL5 in invasionproliferation and proportion of CD44+CD24minus phenotype ofMCF-7 cells and correlation of CCL5 andCCR5 expressionwithbreast cancer progressionrdquo Oncology Reports vol 21 no 4 pp1113ndash1121 2009

[104] W B Fang I Jokar A Zou D Lambert P Dendukuri and NCheng ldquoCCL2CCR2 chemokine signaling coordinates survivaland motility of breast cancer cells through Smad3 protein- andp4244 mitogen-activated protein kinase (MAPK)-dependentmechanismsrdquo The Journal of Biological Chemistry vol 287 pp36593ndash36608 2012

[105] J L Steiner and E A Murphy ldquoImportance of chemokine (CC-motif) ligand 2 in breast cancerrdquo The International Journal ofBiological Markers vol 27 no 3 pp e179ndashe185 2012

[106] X Lu and Y Kang ldquoChemokine (C-C Motif) ligand 2 engagesCCR2+ stromal cells of monocytic origin to promote breastcancer metastasis to lung and bonerdquo The Journal of BiologicalChemistry vol 284 no 42 pp 29087ndash29096 2009

[107] T T Murooka R Rahbar and E N Fish ldquoCCL5 promotesproliferation of MCF-7 cells through mTOR-dependent mRNAtranslationrdquo Biochemical and Biophysical Research Communica-tions vol 387 no 2 pp 381ndash386 2009

[108] M Velasco-Velazquez and R G Pestell ldquoThe CCL5CCR5 axispromotes metastasis in basal breast cancerrdquo Oncoimmunologyvol 2 no 4 Article ID e23660 2013

[109] G Luboshits S Shina O Kaplan et al ldquoElevated expressionof the CC chemokine regulated on activation normal T cellexpressed and secreted (RANTES) in advanced breast carci-nomardquo Cancer Research vol 59 no 18 pp 4681ndash4687 1999

[110] M Cerna A Narsanska V Treska R Kucera and O TopolcanldquoIGF1 and tumor markers in different breast cancer stagesrdquoRozhledy v Chirurgii vol 90 no 12 pp 688ndash694 2011

[111] S Mezi L Todi E Orsi A Angeloni and P Mancini ldquoInvolve-ment of the Src-cortactin pathway inmigration induced by IGF-1 and EGF in human breast cancer cellsrdquo International Journalof Oncology vol 41 no 6 pp 2128ndash2138

[112] R Kucera M Cerna A Narsanska et al ldquoGrowth factorsand breast tumors comparison of selected growth factors withtraditional tumor markersrdquo Anticancer Research vol 31 no 12pp 4653ndash4656 2011

[113] H H Ahmed F MMetwally E S MahdyW G Shosha and SS Ramadan ldquoClinical value of serum hepatocyte growth factor

B-cell lymphoma-2 and nitric oxide in primary breast cancerpatientsrdquo European Review for Medical and PharmacologicalSciences vol 16 p 958 2012

[114] H Arias-Pulido N Chaher Y Gong C Qualls J Vargas andM Royce ldquoTumor stromal vascular endothelial growth factorA is predictive of poor outcome in inflammatory breast cancerrdquoBMC Cancer vol 12 p 298 2012

[115] J MM Oda K B de Oliveira R L Guembarovski KW A deLima A C D D Herrera A L Guembarovski et al ldquoTGF-120573 polymorphism and its expression correlated with CXCR4expression in human breast cancerrdquoMolecular Biology Reportsvol 39 no 12 pp 10131ndash10137 2012

[116] N Dumont and C L Arteaga ldquoTransforming growth factor-120573 and breast cancer tumor promoting effects of transforminggrowth factor-120573rdquo Breast Cancer Research vol 2 no 2 pp 125ndash132 2000

[117] S-M Sheen-Chen H-S Chen C-W Sheen H-L Eng andW-J Chen ldquoSerum levels of transforming growth factor 1205731 inpatients with breast cancerrdquo Archives of Surgery vol 136 no 8pp 937ndash940 2001

[118] J D Figueroa K C Flanders M Garcia-Closas et al ldquoExpres-sion of TGF-120573 signaling factors in invasive breast cancersrelationships with age at diagnosis and tumor characteristicsrdquoBreast Cancer Research and Treatment vol 121 no 3 pp 727ndash735 2010

[119] E M de Kruijf T J Dekker L J Hawinkels H Putter V TSmit J R Kroep et al ldquoThe prognostic role of TGF-120573 signalingpathway in breast cancer patientsrdquo Annals of Oncology vol 24no 2 pp 384ndash390 2013

[120] M Eilers and R N Eisenman ldquoMycrsquos broad reachrdquo Genes andDevelopment vol 22 no 20 pp 2755ndash2766 2008

[121] C V Dang ldquoc-Myc target genes involved in cell growthapoptosis andmetabolismrdquoMolecular and Cellular Biology vol19 no 1 pp 1ndash11 1999

[122] N Todorovic-Rakovic Z Neskovic-Konstantinovic and DNikolic-Vukosavljevic ldquoC-myc as a predictive marker forchemotherapy in metastatic breast cancerrdquo Clinical and Experi-mental Medicine vol 12 no 4 pp 217ndash223 2012

[123] A D Singhi A Cimino-Mathews R B Jenkins et al ldquoMYCgene amplification is often acquired in lethal distant breastcancer metastases of unamplified primary tumorsrdquo ModernPathology vol 25 no 3 pp 378ndash387 2012

[124] D Horiuchi L Kusdra N E Huskey S Chandriani ME Lenburg A M Gonzalez-Angulo et al ldquoMYC pathwayactivation in triple-negative breast cancer is synthetic lethalwith CDK inhibitionrdquo Journal of Experimental Medicine vol209 no 4 pp 679ndash696 2012

[125] J K Rummukainen T Salminen J Lundin S Kytola HJoensuu and J J Isola ldquoAmplification of c-myc by fluorescencein situ hybridization in a population-based breast cancer tissuearrayrdquoModern Pathology vol 14 no 10 pp 1030ndash1035 2001

[126] MOloomi S BouzariMAMohagheghi andHKhodayaran-Tehrani ldquoMolecular markers in peripheral blood of iranianwomen with breast cancerrdquo Cancer Microenviron vol 6 no 1pp 109ndash116 2013

[127] M Sahin E Sahin and S Koksoy ldquoRegulatory T cells in canceran overview and perspectives on cyclooxygenase-2 and Foxp3DNAmethylationrdquoHuman Immunology vol 74 no 9 pp 1061ndash1068 2013

[128] M A E Watanabe J M M Oda M K Amarante and J CesarVoltarelli ldquoRegulatory T cells and breast cancer implications

12 Disease Markers

for immunopathogenesisrdquo Cancer and Metastasis Reviews vol29 no 4 pp 569ndash579 2010

[129] L Wang R Liu W Li et al ldquoSomatic single hits inactivate theX-linked tumor suppressor FOXP3 in the prostaterdquoCancer Cellvol 16 no 4 pp 336ndash346 2009

[130] T Zuo R Liu H Zhang et al ldquoFOXP3 is a novel transcriptionalrepressor for the breast cancer oncogene SKP2rdquo The Journal ofClinical Investigation vol 117 no 12 pp 3765ndash3773 2007

[131] A Balsari A Merlo P Casalini et al ldquoFOXP3 expression andoverall survival in breast cancerrdquo Journal of Clinical Oncologyvol 27 no 11 pp 1746ndash1752 2009

[132] G-Y Chen C Chen L Wang X Chang P Zheng and Y LiuldquoCutting edge broad expression of the FoxP3 locus in epithelialcells a caution against early interpretation of fatal inflammatorydiseases following in vivo depletion of FoxP3-expressing cellsrdquoJournal of Immunology vol 180 no 8 pp 5163ndash5166 2008

[133] T Zuo L Wang C Morrison et al ldquoFOXP3 is an X-linkedbreast cancer suppressor gene and an important repressor ofthe HER-2ErbB2 oncogenerdquo Cell vol 129 no 7 pp 1275ndash12862007

[134] D Overbeck-Zubrzycka S Ali J Kirby and T LennardldquoFOXP3 transcription factor regulates metastatic spread ofbreast cancer via control of expression of CXCR4 chemokinereceptorrdquo British Journal of Surgery vol 98 no 1 pp 84ndash852011

[135] J RHarvey PMellorH Eldaly TW J Lennard J AKirby andS Ali ldquoInhibition of CXCR4-mediated breast cancermetastasisa potential role for heparinoidsrdquo Clinical Cancer Research vol13 no 5 pp 1562ndash1570 2007

[136] P Mellor J R Harvey K J Murphy et al ldquoModulatory effectsof heparin and short-length oligosaccharides of heparin on themetastasis and growth of LMDMDA-MB 231 breast cancer cellsin vivordquo British Journal of Cancer vol 97 no 6 pp 761ndash7682007

[137] M V Iorio M Ferracin C-G Liu et al ldquoMicroRNA geneexpression deregulation in human breast cancerrdquo CancerResearch vol 65 no 16 pp 7065ndash7070 2005

[138] S W Fu L Chen and Y G Man ldquomiRNA biomarkers in breastcancer detection andmanagementrdquo Journal of Cancer vol 2 pp116ndash122 2011

[139] D P Bartel ldquoMicroRNAs genomics biogenesis mechanismand functionrdquo Cell vol 116 no 2 pp 281ndash297 2004

[140] R I Gregory and R Shiekhattar ldquoMicroRNA biogenesis andcancerrdquo Cancer Research vol 65 no 9 pp 3509ndash3512 2005

[141] D D Taylor and C Gercel-Taylor ldquoMicroRNA signatures oftumor-derived exosomes as diagnostic biomarkers of ovariancancerrdquo Gynecologic Oncology vol 110 no 1 pp 13ndash21 2008

[142] L J Chin and F J Slack ldquoA truth serum for cancer microRNAshave major potential as cancer biomarkersrdquo Cell Research vol18 no 10 pp 983ndash984 2008

[143] P S Mitchell R K Parkin E M Kroh et al ldquoCirculatingmicroRNAs as stable blood-based markers for cancer detec-tionrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 105 no 30 pp 10513ndash10518 2008

[144] D P Bartel ldquoMicroRNAs target recognition and regulatoryfunctionsrdquo Cell vol 136 no 2 pp 215ndash233 2009

[145] D J Guarnieri and R J Dileone ldquoMicroRNAs a new class ofgene regulatorsrdquo Annals of Medicine vol 40 no 3 pp 197ndash2082008

[146] XWuG Somlo Y Yu et al ldquoDe novo sequencing of circulatingmiRNAs identifies novel markers predicting clinical outcome

of locally advanced breast cancerrdquo Journal of TranslationalMedicine vol 10 no 1 article 42 2012

[147] B Wang H Wang and Z Yang ldquoMiR-122 inhibits cell prolif-eration and tumorigenesis of breast cancer by targeting IGF1RrdquoPloS ONE vol 7 no 10 Article ID e47053 2012

[148] L Shen J Li L Xu et al ldquomiR-497 induces apoptosis of breastcancer cells by targeting Bcl-wrdquo Experimental and TherapeuticMedicine vol 3 no 3 pp 475ndash480 2012

[149] C M Croce ldquoCauses and consequences of microRNA dysreg-ulation in cancerrdquo Nature Reviews Genetics vol 10 no 10 pp704ndash714 2009

[150] Q Huang K Gumireddy M Schrier et al ldquoThe microRNAsmiR-373 and miR-520c promote tumour invasion and metasta-sisrdquo Nature Cell Biology vol 10 no 2 pp 202ndash210 2008

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawi Publishing Corporation httpwwwhindawicom Volume 2013

The Scientific World Journal

International Journal of

EndocrinologyHindawi Publishing Corporationhttpwwwhindawicom

Volume 2013

ISRN Anesthesiology

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OncologyJournal of

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PPARRe sea rch

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OphthalmologyJournal of

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ISRN AIDS

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BioMed Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

ISRN Addiction

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Computational and Mathematical Methods in Medicine

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Journal of

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Evidence-Based Complementary and Alternative Medicine

Volume 2013Hindawi Publishing Corporationhttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

ISRN Biomarkers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

MEDIATORSINFLAMMATION

of

Disease Markers 9

[33] D J Slamon B Leyland-Jones S Shak et al ldquoUse of chemother-apy plus a monoclonal antibody against her2 for metastaticbreast cancer that overexpresses HER2rdquo The New EnglandJournal of Medicine vol 344 no 11 pp 783ndash792 2001

[34] M A Molina J Codony-Servat J Albanell F Rojo J Arribasand J Baselga ldquoTrastuzumab (Herceptin) a humanized anti-HER2 receptor monoclonal antibody inhibits basal and acti-vated HER2 ectodomain cleavage in breast cancer cellsrdquo CancerResearch vol 61 no 12 pp 4744ndash4749 2001

[35] C A Hudis ldquoTrastuzumabmdashmechanism of action and use inclinical practicerdquoTheNew England Journal of Medicine vol 357no 1 pp 39ndash51 2007

[36] S R D Johnston and A Leary ldquoLapatinib a novel EGFRHER2tyrosine kinase inhibitor for cancerrdquoDrugs of Today vol 42 no7 pp 441ndash453 2006

[37] T Narita H Funahashi Y Satoh and H Takagi ldquoC-erbB-2protein in the sera of breast cancer patientsrdquo Breast CancerResearch and Treatment vol 24 no 2 pp 97ndash102 1992

[38] V H C Bramwell G S Doig A B Tuck et al ldquoChangesover time of extracellular domain of HER2 (ECDHER2) serumlevels have prognostic value in metastatic breast cancerrdquo BreastCancer Research andTreatment vol 114 no 3 pp 503ndash511 2009

[39] L-D Tan Y-Y Xu Y Yu X-Q Li Y Chen and Y-MFeng ldquoSerum HER2 level measured by dot blot a valid andinexpensive assay for monitoring breast cancer progressionrdquoPLoS ONE vol 6 no 4 Article ID e18764 2011

[40] R Dent M Trudeau K I Pritchard et al ldquoTriple-negativebreast cancer clinical features and patterns of recurrencerdquoClinical Cancer Research vol 13 no 15 pp 4429ndash4434 2007

[41] K A Cadoo T A Traina and T A King ldquoAdvances inmolecular and clinical subtyping of breast cancer and theirimplications for therapyrdquo Surgical Oncology Clinics of NorthAmerica vol 22 p 823 2013

[42] E Y Cho M H Chang Y L Choi et al ldquoPotential candidatebiomarkers for heterogeneity in triple-negative breast cancer(TNBC)rdquo Cancer Chemotherapy and Pharmacology vol 68 no3 pp 753ndash761 2011

[43] T Soslashrlie R Tibshirani J Parker et al ldquoRepeated observationof breast tumor subtypes in independent gene expression datasetsrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 100 no 14 pp 8418ndash8423 2003

[44] J Gerdes H Lemke and H Baisch ldquoCell cycle analysis of a cellproliferation associated human nuclear antigen defined by themonoclonal antibody Ki-67rdquo Journal of Immunology vol 133no 4 pp 1710ndash1715 1984

[45] F Reyal M A Bollet M Caly et al ldquoRespective prognosticvalue of genomic grade and histological proliferation markersin early stage (pN0) breast carcinomardquo PLoS ONE vol 7 no 4Article ID e35184 2012

[46] P Vielh S Chevillard V Mosseri B Donatini and H Magde-lenat ldquoKi67 index and S-phase fraction in human breast carci-nomas Comparison and correlations with prognostic factorsrdquoAmerican Journal of Clinical Pathology vol 94 no 6 pp 681ndash686 1990

[47] T Soslashrlie Y Wang C Xiao et al ldquoDistinct molecular mecha-nisms underlying clinically relevant subtypes of breast cancergene expression analyses across three different platformsrdquo BMCGenomics vol 7 article 127 2006

[48] A V Patil R Singhai R S Bhamre and V W Patil ldquoKi-67biomarker in breast cancer of Indian womenrdquo North AmericanJournal of Medical Sciences vol 3 no 3 pp 119ndash128 2011

[49] K Tawfik B F Kimler M K Davis F Fan and O TawfikldquoKi-67 expression in axillary lymph node metastases in breastcancer is prognostically significantrdquo Human Pathology vol 44no 1 pp 39ndash46 2013

[50] E Luporsi F Andre F Spyratos et al ldquoKi-67 level of evidenceand methodological considerations for its role in the clinicalmanagement of breast cancer analytical and critical reviewrdquoBreast Cancer Research and Treatment vol 132 no 3 pp 895ndash915 2012

[51] S P Hussain and C C Harris ldquop53 biological network atthe crossroads of the cellular-stress response pathway andmolecular carcinogenesisrdquo Journal of Nippon Medical Schoolvol 73 no 2 pp 54ndash64 2006

[52] T Soslashrlie C M Perou R Tibshirani et al ldquoGene expressionpatterns of breast carcinomas distinguish tumor subclasses withclinical implicationsrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 98 no 19 pp 10869ndash10874 2001

[53] D C Allred G M Clark R Elledge et al ldquoAssociation of p53protein expressionwith tumor cell proliferation rate and clinicaloutcome in node-negative breast cancerrdquo Journal of the NationalCancer Institute vol 85 no 3 pp 200ndash206 1993

[54] A Dumay J P Feugeas E Wittmer J Lehmann-Che PBertheau M Espie et al ldquoDistinct tumor protein p53 mutantsin breast cancer subgroupsrdquo International Journal of Cancer vol132 no 5 pp 1227ndash1231 2013

[55] R M Elledge G M Clark S A W Fuqua Y-Y Yu and DC Allred ldquop53 protein accumulation detected by five differentantibodies relationship to prognosis and heat shock protein 70in breast cancerrdquo Cancer Research vol 54 no 14 pp 3752ndash37571994

[56] M Lacroix ldquoSignificance detection and markers of dissemi-nated breast cancer cellsrdquo Endocrine-Related Cancer vol 13 no4 pp 1033ndash1067 2006

[57] E Vizcarra A Lluch R Cibrian et al ldquoValue of CA 153 inbreast cancer and comparison with CEA and TPA a studyof specificity in disease-free follow-up patients and sensitivityin patients at diagnosis of the first metastasisrdquo Breast CancerResearch and Treatment vol 37 no 3 pp 209ndash216 1996

[58] J G Geraghty E C Coveney F Sherry N J Ohiggins and MJ Duffy ldquoCa-15-3 in patients with locoregional and metastaticbreast-carcinomardquo Cancer vol 70 p 2831 1992

[59] F G Ebeling P StieberMUntch et al ldquoSerumCEAandCA 15-3 as prognostic factors in primary breast cancerrdquo British Journalof Cancer vol 86 no 8 pp 1217ndash1222 2002

[60] J AThompson FGrunert andWZimmermann ldquoCarcinoem-bryonic antigen gene family molecular biology and clinicalperspectivesrdquo Journal of Clinical Laboratory Analysis vol 5 no5 pp 344ndash366 1991

[61] R Molina J M Auge B Farrus et al ldquoProspective evaluationof Carcinoembryonic Antigen (CEA) and carbohydrate antigen153 (CA 153) in patients with primary locoregional breastcancerrdquo Clinical Chemistry vol 56 no 7 pp 1148ndash1157 2010

[62] MUehara T Kinoshita THojo S Akashi-Tanaka E Iwamotoand T Fukutomi ldquoLong-term prognostic study of carcinoem-bryonic antigen (CEA) and carbohydrate antigen 15-3 (CA 15-3)in breast cancerrdquo International Journal of Clinical Oncology vol13 no 5 pp 447ndash451 2008

[63] A Thathiah and D D Carson ldquoMT1-MMP mediates MUC1shedding independent of TACEADAM17rdquo Biochemical Jour-nal vol 382 no 1 pp 363ndash373 2004

10 Disease Markers

[64] C L Hattrup and S J Gendler ldquoStructure and function of thecell surface (tethered) mucinsrdquo Annual Review of Physiologyvol 70 pp 431ndash457 2008

[65] M J Duffy S Shering F Sherry E McDermott and NOrsquoHiggins ldquoCA 15-3 a prognostic marker in breast cancerrdquoInternational Journal of Biological Markers vol 15 no 4 pp330ndash333 2000

[66] M T Sandri M Salvatici E Botteri et al ldquoPrognostic roleof CA153 in 7942 patients with operable breast cancerrdquo BreastCancer Research and Treatment vol 132 no 1 pp 317ndash326 2012

[67] G A Mendes F C R Sturmer and D L Basegio ldquoUtilizacaodosmarcadores CA15 3 e CEAno seguimento de pacientes comneoplasia mamariardquo NewsLab vol 102 p 7 2010

[68] W Jager K Eibner B Loffler S Gleixner and S Kramer ldquoSerialCEA and CA 15-3 measurements during follow-up of breastcancer patientsrdquo Anticancer Research vol 20 no 6 pp 5179ndash5182 2000

[69] P L Welcsh K N Owens and M-C King ldquoInsights into thefunctions of BRCA1 and BRCA2rdquoTrends in Genetics vol 16 no2 pp 69ndash74 2000

[70] A R Venkitaraman ldquoCancer susceptibility and the functions ofBRCA1 and BRCA2rdquo Cell vol 108 no 2 pp 171ndash182 2002

[71] D Bertwistle and A Ashworth ldquoFunctions of the BRCA1 endBRCA2 genesrdquo Current Opinion in Genetics and Developmentvol 8 no 1 pp 14ndash20 1998

[72] N Rahman and M R Stratton ldquoThe genetics of breast cancersusceptibilityrdquo Annual Review of Genetics vol 32 pp 95ndash1211998

[73] I Shapira R J GrallaM Akerman L RWeiselberg V S JohnH Raftopoulos et al Does maternal Or paternal inheritance ofBRCA Mutation Affect the Age of Cancer Diagnosis in MeetingASCOA Texas 2011

[74] N Senst M Llacuachaqui J Lubinski H Lynch S Armel SNeuhausen et al ldquoParental origin of mutation and the risk ofbreast cancer in a prospective study of women with a BRCA1or BRCA2mutationrdquo Clinical Genetics vol 84 no 1 pp 43ndash462013

[75] N Ikeda Y Miyoshi K Yoneda E Shiba Y Sekihara MKinoshita et al ldquoFrequency of BRCA1 and BRCA2 germlinemutations in Japanese breast cancer familiesrdquo InternationalJournal of Cancer vol 91 no 1 pp 83ndash88 2001

[76] M E Robson ldquoTreatment of hereditary breast cancerrdquo Seminarsin Oncology vol 34 no 5 pp 384ndash391 2007

[77] G F Schwartz K S Hughes H T Lynch et al ldquoProceedingsof the international consensus conference on breast cancer riskgenetics amp risk management April 2007rdquo Cancer vol 113 no10 pp 2627ndash2637 2008

[78] M VanstoneW Chow L Lester P Ainsworth J Nisker andMBrackstone ldquoRecognizingBRCAgenemutation risk subsequentto breast cancer diagnosis in southwestern Ontariordquo CanadianFamily Physician vol 58 no 5 pp E258ndashE266 2012

[79] T R Rebbeck T Friebel H T Lynch et al ldquoBilateral prophylac-ticmastectomy reduces breast cancer risk inBRCA1 and BRCA2mutation carriers the PROSE study grouprdquo Journal of ClinicalOncology vol 22 no 6 pp 1055ndash1062 2004

[80] P Apostolou and F Fostira ldquoHereditary breast cancer the eraof new susceptibility genesrdquo BioMed Research International vol2013 Article ID 747318 2013

[81] G-LMoldovan B Pfander and S Jentsch ldquoPCNA themaestroof the replication forkrdquo Cell vol 129 no 4 pp 665ndash679 2007

[82] R Bravo and H Macdonald-Bravo ldquoExistence of two popula-tions of cyclinproliferating cell nuclear antigen during the cellcycle associationwithDNAreplication sitesrdquoTheJournal of CellBiology vol 105 no 4 pp 1549ndash1554 1987

[83] C W Elston and I O Ellis ldquoPathological prognostic factorsin breast cancer I The value of histological grade in breastcancer experience from a large study with long-term follow-uprdquo Histopathology vol 19 no 5 pp 403ndash410 1991

[84] H Zhao P-C Ho Y-H Lo et al ldquoInteraction of proliferationcell nuclear antigen (PCNA) with c-Abl in cell proliferation andresponse to DNA damages in breast cancerrdquo PLoS ONE vol 7no 1 Article ID e29416 2012

[85] H Zhao Y-H Lo LMa et al ldquoTargeting tyrosine phosphoryla-tion of pcna inhibits prostate cancer growthrdquoMolecular CancerTherapeutics vol 10 no 1 pp 29ndash36 2011

[86] M N Aoki M K Amarante J M M Oda and M A EWatanabe ldquoCaveolin involvement and modulation in breastcancerrdquoMini-Reviews in Medicinal Chemistry vol 11 no 13 pp1143ndash1152 2011

[87] R Hnasko and M P Lisanti ldquoThe biology of caveolae lessonsfrom caveolin knockout mice and implications for humandiseaserdquo Molecular Interventions vol 3 no 8 pp 445ndash4642003

[88] S E Elsheikh A R Green E A Rakha et al ldquoCaveolin 1and caveolin 2 are associated with breast cancer basal-like andtriple-negative immunophenotyperdquo British Journal of Cancervol 99 no 2 pp 327ndash334 2008

[89] J A Karam Y Lotan C G Roehrborn R Ashfaq P IKarakiewicz and S F Shariat ldquoCaveolin-I overexpression isassociated with aggressive prostate cancer recurrencerdquo Prostatevol 67 no 6 pp 614ndash622 2007

[90] C-CHo S-HKuo P-HHuangH-YHuang andC-HYangldquoCaveolin-1 expression is significantly associated with drugresistance and poor prognosis in advanced non-small cell lungcancer patients treated with gemcitabine-based chemotherapyrdquoLung Cancer vol 59 no 1 pp 105ndash110 2008

[91] V Barresi S Cerasoli G Paioli et al ldquoCaveolin-1 in menin-giomas expression and clinico-pathological correlationsrdquo ActaNeuropathologica vol 112 no 5 pp 617ndash626 2006

[92] M Kucia R Reca K Miekus et al ldquoTrafficking of normalstem cells and metastasis of cancer stem cells involve similarmechanisms pivotal role of the SDF-1-CXCR4 axisrdquo Stem Cellsvol 23 no 7 pp 879ndash894 2005

[93] A Muller B Homey H Soto et al ldquoInvolvement of chemokinereceptors in breast cancermetastasisrdquoNature vol 410 no 6824pp 50ndash56 2001

[94] D Mukherjee and J Zhao ldquoThe Role of chemokine receptorCXCR4 in breast cancermetastasisrdquoAmerican Journal of CancerResearch vol 3 no 1 pp 46ndash57 2013

[95] T Schioppa B Uranchimeg A Saccani et al ldquoRegulationof the chemokine receptor CXCR4 by hypoxiardquo Journal ofExperimental Medicine vol 198 no 9 pp 1391ndash1402 2003

[96] H Kang G Watkins C Parr A Douglas-Jones R E Manseland W G Jiang ldquoStromal cell derived factor-1 its influence oninvasiveness and migration of breast cancer cells in vitro andits association with prognosis and survival in human breastcancerrdquo Breast Cancer Research vol 7 no 4 pp R402ndashR4102005

[97] Q D Chu L Panu N T Holm B D L Li L W Johnsonand S Zhang ldquoHigh chemokine receptor CXCR4 level intriple negative breast cancer specimens predicts poor clinical

Disease Markers 11

outcomerdquo Journal of Surgical Research vol 159 no 2 pp 689ndash695 2010

[98] H W Chen C W Du X L Wei U S Khoo and G J ZhangldquoCytoplasmic CXCR4 high-expression exhibits distinct poorclinicopathological characteristics and predicts poor prognosisin triple-negative breast cancerrdquo Current Molecular Medicinevol 13 no 3 pp 410ndash416 2013

[99] J-K Li L Yu Y Shen L-S Zhou Y-C Wang and J-HZhang ldquoInhibition of CXCR4 activity with AMD3100 decreasesinvasion of human colorectal cancer cells in vitrordquo WorldJournal of Gastroenterology vol 14 no 15 pp 2308ndash2313 2008

[100] K Christopherson II and R Hromas ldquoChemokine regulation ofnormal and pathologic immune responsesrdquo Stem Cells vol 19no 5 pp 388ndash396 2001

[101] C R Mackay ldquoChemokines immunologyrsquos high impact fac-torsrdquo Nature Immunology vol 2 no 2 pp 95ndash101 2001

[102] A Zlotnik O Yoshie and H Nomiyama ldquoThe chemokineand chemokine receptor superfamilies and their molecularevolutionrdquo Genome Biology vol 7 no 12 article 243 2006

[103] Y Zhang F Yao X Yao et al ldquoRole of CCL5 in invasionproliferation and proportion of CD44+CD24minus phenotype ofMCF-7 cells and correlation of CCL5 andCCR5 expressionwithbreast cancer progressionrdquo Oncology Reports vol 21 no 4 pp1113ndash1121 2009

[104] W B Fang I Jokar A Zou D Lambert P Dendukuri and NCheng ldquoCCL2CCR2 chemokine signaling coordinates survivaland motility of breast cancer cells through Smad3 protein- andp4244 mitogen-activated protein kinase (MAPK)-dependentmechanismsrdquo The Journal of Biological Chemistry vol 287 pp36593ndash36608 2012

[105] J L Steiner and E A Murphy ldquoImportance of chemokine (CC-motif) ligand 2 in breast cancerrdquo The International Journal ofBiological Markers vol 27 no 3 pp e179ndashe185 2012

[106] X Lu and Y Kang ldquoChemokine (C-C Motif) ligand 2 engagesCCR2+ stromal cells of monocytic origin to promote breastcancer metastasis to lung and bonerdquo The Journal of BiologicalChemistry vol 284 no 42 pp 29087ndash29096 2009

[107] T T Murooka R Rahbar and E N Fish ldquoCCL5 promotesproliferation of MCF-7 cells through mTOR-dependent mRNAtranslationrdquo Biochemical and Biophysical Research Communica-tions vol 387 no 2 pp 381ndash386 2009

[108] M Velasco-Velazquez and R G Pestell ldquoThe CCL5CCR5 axispromotes metastasis in basal breast cancerrdquo Oncoimmunologyvol 2 no 4 Article ID e23660 2013

[109] G Luboshits S Shina O Kaplan et al ldquoElevated expressionof the CC chemokine regulated on activation normal T cellexpressed and secreted (RANTES) in advanced breast carci-nomardquo Cancer Research vol 59 no 18 pp 4681ndash4687 1999

[110] M Cerna A Narsanska V Treska R Kucera and O TopolcanldquoIGF1 and tumor markers in different breast cancer stagesrdquoRozhledy v Chirurgii vol 90 no 12 pp 688ndash694 2011

[111] S Mezi L Todi E Orsi A Angeloni and P Mancini ldquoInvolve-ment of the Src-cortactin pathway inmigration induced by IGF-1 and EGF in human breast cancer cellsrdquo International Journalof Oncology vol 41 no 6 pp 2128ndash2138

[112] R Kucera M Cerna A Narsanska et al ldquoGrowth factorsand breast tumors comparison of selected growth factors withtraditional tumor markersrdquo Anticancer Research vol 31 no 12pp 4653ndash4656 2011

[113] H H Ahmed F MMetwally E S MahdyW G Shosha and SS Ramadan ldquoClinical value of serum hepatocyte growth factor

B-cell lymphoma-2 and nitric oxide in primary breast cancerpatientsrdquo European Review for Medical and PharmacologicalSciences vol 16 p 958 2012

[114] H Arias-Pulido N Chaher Y Gong C Qualls J Vargas andM Royce ldquoTumor stromal vascular endothelial growth factorA is predictive of poor outcome in inflammatory breast cancerrdquoBMC Cancer vol 12 p 298 2012

[115] J MM Oda K B de Oliveira R L Guembarovski KW A deLima A C D D Herrera A L Guembarovski et al ldquoTGF-120573 polymorphism and its expression correlated with CXCR4expression in human breast cancerrdquoMolecular Biology Reportsvol 39 no 12 pp 10131ndash10137 2012

[116] N Dumont and C L Arteaga ldquoTransforming growth factor-120573 and breast cancer tumor promoting effects of transforminggrowth factor-120573rdquo Breast Cancer Research vol 2 no 2 pp 125ndash132 2000

[117] S-M Sheen-Chen H-S Chen C-W Sheen H-L Eng andW-J Chen ldquoSerum levels of transforming growth factor 1205731 inpatients with breast cancerrdquo Archives of Surgery vol 136 no 8pp 937ndash940 2001

[118] J D Figueroa K C Flanders M Garcia-Closas et al ldquoExpres-sion of TGF-120573 signaling factors in invasive breast cancersrelationships with age at diagnosis and tumor characteristicsrdquoBreast Cancer Research and Treatment vol 121 no 3 pp 727ndash735 2010

[119] E M de Kruijf T J Dekker L J Hawinkels H Putter V TSmit J R Kroep et al ldquoThe prognostic role of TGF-120573 signalingpathway in breast cancer patientsrdquo Annals of Oncology vol 24no 2 pp 384ndash390 2013

[120] M Eilers and R N Eisenman ldquoMycrsquos broad reachrdquo Genes andDevelopment vol 22 no 20 pp 2755ndash2766 2008

[121] C V Dang ldquoc-Myc target genes involved in cell growthapoptosis andmetabolismrdquoMolecular and Cellular Biology vol19 no 1 pp 1ndash11 1999

[122] N Todorovic-Rakovic Z Neskovic-Konstantinovic and DNikolic-Vukosavljevic ldquoC-myc as a predictive marker forchemotherapy in metastatic breast cancerrdquo Clinical and Experi-mental Medicine vol 12 no 4 pp 217ndash223 2012

[123] A D Singhi A Cimino-Mathews R B Jenkins et al ldquoMYCgene amplification is often acquired in lethal distant breastcancer metastases of unamplified primary tumorsrdquo ModernPathology vol 25 no 3 pp 378ndash387 2012

[124] D Horiuchi L Kusdra N E Huskey S Chandriani ME Lenburg A M Gonzalez-Angulo et al ldquoMYC pathwayactivation in triple-negative breast cancer is synthetic lethalwith CDK inhibitionrdquo Journal of Experimental Medicine vol209 no 4 pp 679ndash696 2012

[125] J K Rummukainen T Salminen J Lundin S Kytola HJoensuu and J J Isola ldquoAmplification of c-myc by fluorescencein situ hybridization in a population-based breast cancer tissuearrayrdquoModern Pathology vol 14 no 10 pp 1030ndash1035 2001

[126] MOloomi S BouzariMAMohagheghi andHKhodayaran-Tehrani ldquoMolecular markers in peripheral blood of iranianwomen with breast cancerrdquo Cancer Microenviron vol 6 no 1pp 109ndash116 2013

[127] M Sahin E Sahin and S Koksoy ldquoRegulatory T cells in canceran overview and perspectives on cyclooxygenase-2 and Foxp3DNAmethylationrdquoHuman Immunology vol 74 no 9 pp 1061ndash1068 2013

[128] M A E Watanabe J M M Oda M K Amarante and J CesarVoltarelli ldquoRegulatory T cells and breast cancer implications

12 Disease Markers

for immunopathogenesisrdquo Cancer and Metastasis Reviews vol29 no 4 pp 569ndash579 2010

[129] L Wang R Liu W Li et al ldquoSomatic single hits inactivate theX-linked tumor suppressor FOXP3 in the prostaterdquoCancer Cellvol 16 no 4 pp 336ndash346 2009

[130] T Zuo R Liu H Zhang et al ldquoFOXP3 is a novel transcriptionalrepressor for the breast cancer oncogene SKP2rdquo The Journal ofClinical Investigation vol 117 no 12 pp 3765ndash3773 2007

[131] A Balsari A Merlo P Casalini et al ldquoFOXP3 expression andoverall survival in breast cancerrdquo Journal of Clinical Oncologyvol 27 no 11 pp 1746ndash1752 2009

[132] G-Y Chen C Chen L Wang X Chang P Zheng and Y LiuldquoCutting edge broad expression of the FoxP3 locus in epithelialcells a caution against early interpretation of fatal inflammatorydiseases following in vivo depletion of FoxP3-expressing cellsrdquoJournal of Immunology vol 180 no 8 pp 5163ndash5166 2008

[133] T Zuo L Wang C Morrison et al ldquoFOXP3 is an X-linkedbreast cancer suppressor gene and an important repressor ofthe HER-2ErbB2 oncogenerdquo Cell vol 129 no 7 pp 1275ndash12862007

[134] D Overbeck-Zubrzycka S Ali J Kirby and T LennardldquoFOXP3 transcription factor regulates metastatic spread ofbreast cancer via control of expression of CXCR4 chemokinereceptorrdquo British Journal of Surgery vol 98 no 1 pp 84ndash852011

[135] J RHarvey PMellorH Eldaly TW J Lennard J AKirby andS Ali ldquoInhibition of CXCR4-mediated breast cancermetastasisa potential role for heparinoidsrdquo Clinical Cancer Research vol13 no 5 pp 1562ndash1570 2007

[136] P Mellor J R Harvey K J Murphy et al ldquoModulatory effectsof heparin and short-length oligosaccharides of heparin on themetastasis and growth of LMDMDA-MB 231 breast cancer cellsin vivordquo British Journal of Cancer vol 97 no 6 pp 761ndash7682007

[137] M V Iorio M Ferracin C-G Liu et al ldquoMicroRNA geneexpression deregulation in human breast cancerrdquo CancerResearch vol 65 no 16 pp 7065ndash7070 2005

[138] S W Fu L Chen and Y G Man ldquomiRNA biomarkers in breastcancer detection andmanagementrdquo Journal of Cancer vol 2 pp116ndash122 2011

[139] D P Bartel ldquoMicroRNAs genomics biogenesis mechanismand functionrdquo Cell vol 116 no 2 pp 281ndash297 2004

[140] R I Gregory and R Shiekhattar ldquoMicroRNA biogenesis andcancerrdquo Cancer Research vol 65 no 9 pp 3509ndash3512 2005

[141] D D Taylor and C Gercel-Taylor ldquoMicroRNA signatures oftumor-derived exosomes as diagnostic biomarkers of ovariancancerrdquo Gynecologic Oncology vol 110 no 1 pp 13ndash21 2008

[142] L J Chin and F J Slack ldquoA truth serum for cancer microRNAshave major potential as cancer biomarkersrdquo Cell Research vol18 no 10 pp 983ndash984 2008

[143] P S Mitchell R K Parkin E M Kroh et al ldquoCirculatingmicroRNAs as stable blood-based markers for cancer detec-tionrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 105 no 30 pp 10513ndash10518 2008

[144] D P Bartel ldquoMicroRNAs target recognition and regulatoryfunctionsrdquo Cell vol 136 no 2 pp 215ndash233 2009

[145] D J Guarnieri and R J Dileone ldquoMicroRNAs a new class ofgene regulatorsrdquo Annals of Medicine vol 40 no 3 pp 197ndash2082008

[146] XWuG Somlo Y Yu et al ldquoDe novo sequencing of circulatingmiRNAs identifies novel markers predicting clinical outcome

of locally advanced breast cancerrdquo Journal of TranslationalMedicine vol 10 no 1 article 42 2012

[147] B Wang H Wang and Z Yang ldquoMiR-122 inhibits cell prolif-eration and tumorigenesis of breast cancer by targeting IGF1RrdquoPloS ONE vol 7 no 10 Article ID e47053 2012

[148] L Shen J Li L Xu et al ldquomiR-497 induces apoptosis of breastcancer cells by targeting Bcl-wrdquo Experimental and TherapeuticMedicine vol 3 no 3 pp 475ndash480 2012

[149] C M Croce ldquoCauses and consequences of microRNA dysreg-ulation in cancerrdquo Nature Reviews Genetics vol 10 no 10 pp704ndash714 2009

[150] Q Huang K Gumireddy M Schrier et al ldquoThe microRNAsmiR-373 and miR-520c promote tumour invasion and metasta-sisrdquo Nature Cell Biology vol 10 no 2 pp 202ndash210 2008

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawi Publishing Corporation httpwwwhindawicom Volume 2013

The Scientific World Journal

International Journal of

EndocrinologyHindawi Publishing Corporationhttpwwwhindawicom

Volume 2013

ISRN Anesthesiology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

OncologyJournal of

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PPARRe sea rch

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

OphthalmologyJournal of

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ISRN AIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

BioMed Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

ISRN Addiction

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Computational and Mathematical Methods in Medicine

ISRN Allergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Journal of

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Evidence-Based Complementary and Alternative Medicine

Volume 2013Hindawi Publishing Corporationhttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

ISRN Biomarkers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

MEDIATORSINFLAMMATION

of

10 Disease Markers

[64] C L Hattrup and S J Gendler ldquoStructure and function of thecell surface (tethered) mucinsrdquo Annual Review of Physiologyvol 70 pp 431ndash457 2008

[65] M J Duffy S Shering F Sherry E McDermott and NOrsquoHiggins ldquoCA 15-3 a prognostic marker in breast cancerrdquoInternational Journal of Biological Markers vol 15 no 4 pp330ndash333 2000

[66] M T Sandri M Salvatici E Botteri et al ldquoPrognostic roleof CA153 in 7942 patients with operable breast cancerrdquo BreastCancer Research and Treatment vol 132 no 1 pp 317ndash326 2012

[67] G A Mendes F C R Sturmer and D L Basegio ldquoUtilizacaodosmarcadores CA15 3 e CEAno seguimento de pacientes comneoplasia mamariardquo NewsLab vol 102 p 7 2010

[68] W Jager K Eibner B Loffler S Gleixner and S Kramer ldquoSerialCEA and CA 15-3 measurements during follow-up of breastcancer patientsrdquo Anticancer Research vol 20 no 6 pp 5179ndash5182 2000

[69] P L Welcsh K N Owens and M-C King ldquoInsights into thefunctions of BRCA1 and BRCA2rdquoTrends in Genetics vol 16 no2 pp 69ndash74 2000

[70] A R Venkitaraman ldquoCancer susceptibility and the functions ofBRCA1 and BRCA2rdquo Cell vol 108 no 2 pp 171ndash182 2002

[71] D Bertwistle and A Ashworth ldquoFunctions of the BRCA1 endBRCA2 genesrdquo Current Opinion in Genetics and Developmentvol 8 no 1 pp 14ndash20 1998

[72] N Rahman and M R Stratton ldquoThe genetics of breast cancersusceptibilityrdquo Annual Review of Genetics vol 32 pp 95ndash1211998

[73] I Shapira R J GrallaM Akerman L RWeiselberg V S JohnH Raftopoulos et al Does maternal Or paternal inheritance ofBRCA Mutation Affect the Age of Cancer Diagnosis in MeetingASCOA Texas 2011

[74] N Senst M Llacuachaqui J Lubinski H Lynch S Armel SNeuhausen et al ldquoParental origin of mutation and the risk ofbreast cancer in a prospective study of women with a BRCA1or BRCA2mutationrdquo Clinical Genetics vol 84 no 1 pp 43ndash462013

[75] N Ikeda Y Miyoshi K Yoneda E Shiba Y Sekihara MKinoshita et al ldquoFrequency of BRCA1 and BRCA2 germlinemutations in Japanese breast cancer familiesrdquo InternationalJournal of Cancer vol 91 no 1 pp 83ndash88 2001

[76] M E Robson ldquoTreatment of hereditary breast cancerrdquo Seminarsin Oncology vol 34 no 5 pp 384ndash391 2007

[77] G F Schwartz K S Hughes H T Lynch et al ldquoProceedingsof the international consensus conference on breast cancer riskgenetics amp risk management April 2007rdquo Cancer vol 113 no10 pp 2627ndash2637 2008

[78] M VanstoneW Chow L Lester P Ainsworth J Nisker andMBrackstone ldquoRecognizingBRCAgenemutation risk subsequentto breast cancer diagnosis in southwestern Ontariordquo CanadianFamily Physician vol 58 no 5 pp E258ndashE266 2012

[79] T R Rebbeck T Friebel H T Lynch et al ldquoBilateral prophylac-ticmastectomy reduces breast cancer risk inBRCA1 and BRCA2mutation carriers the PROSE study grouprdquo Journal of ClinicalOncology vol 22 no 6 pp 1055ndash1062 2004

[80] P Apostolou and F Fostira ldquoHereditary breast cancer the eraof new susceptibility genesrdquo BioMed Research International vol2013 Article ID 747318 2013

[81] G-LMoldovan B Pfander and S Jentsch ldquoPCNA themaestroof the replication forkrdquo Cell vol 129 no 4 pp 665ndash679 2007

[82] R Bravo and H Macdonald-Bravo ldquoExistence of two popula-tions of cyclinproliferating cell nuclear antigen during the cellcycle associationwithDNAreplication sitesrdquoTheJournal of CellBiology vol 105 no 4 pp 1549ndash1554 1987

[83] C W Elston and I O Ellis ldquoPathological prognostic factorsin breast cancer I The value of histological grade in breastcancer experience from a large study with long-term follow-uprdquo Histopathology vol 19 no 5 pp 403ndash410 1991

[84] H Zhao P-C Ho Y-H Lo et al ldquoInteraction of proliferationcell nuclear antigen (PCNA) with c-Abl in cell proliferation andresponse to DNA damages in breast cancerrdquo PLoS ONE vol 7no 1 Article ID e29416 2012

[85] H Zhao Y-H Lo LMa et al ldquoTargeting tyrosine phosphoryla-tion of pcna inhibits prostate cancer growthrdquoMolecular CancerTherapeutics vol 10 no 1 pp 29ndash36 2011

[86] M N Aoki M K Amarante J M M Oda and M A EWatanabe ldquoCaveolin involvement and modulation in breastcancerrdquoMini-Reviews in Medicinal Chemistry vol 11 no 13 pp1143ndash1152 2011

[87] R Hnasko and M P Lisanti ldquoThe biology of caveolae lessonsfrom caveolin knockout mice and implications for humandiseaserdquo Molecular Interventions vol 3 no 8 pp 445ndash4642003

[88] S E Elsheikh A R Green E A Rakha et al ldquoCaveolin 1and caveolin 2 are associated with breast cancer basal-like andtriple-negative immunophenotyperdquo British Journal of Cancervol 99 no 2 pp 327ndash334 2008

[89] J A Karam Y Lotan C G Roehrborn R Ashfaq P IKarakiewicz and S F Shariat ldquoCaveolin-I overexpression isassociated with aggressive prostate cancer recurrencerdquo Prostatevol 67 no 6 pp 614ndash622 2007

[90] C-CHo S-HKuo P-HHuangH-YHuang andC-HYangldquoCaveolin-1 expression is significantly associated with drugresistance and poor prognosis in advanced non-small cell lungcancer patients treated with gemcitabine-based chemotherapyrdquoLung Cancer vol 59 no 1 pp 105ndash110 2008

[91] V Barresi S Cerasoli G Paioli et al ldquoCaveolin-1 in menin-giomas expression and clinico-pathological correlationsrdquo ActaNeuropathologica vol 112 no 5 pp 617ndash626 2006

[92] M Kucia R Reca K Miekus et al ldquoTrafficking of normalstem cells and metastasis of cancer stem cells involve similarmechanisms pivotal role of the SDF-1-CXCR4 axisrdquo Stem Cellsvol 23 no 7 pp 879ndash894 2005

[93] A Muller B Homey H Soto et al ldquoInvolvement of chemokinereceptors in breast cancermetastasisrdquoNature vol 410 no 6824pp 50ndash56 2001

[94] D Mukherjee and J Zhao ldquoThe Role of chemokine receptorCXCR4 in breast cancermetastasisrdquoAmerican Journal of CancerResearch vol 3 no 1 pp 46ndash57 2013

[95] T Schioppa B Uranchimeg A Saccani et al ldquoRegulationof the chemokine receptor CXCR4 by hypoxiardquo Journal ofExperimental Medicine vol 198 no 9 pp 1391ndash1402 2003

[96] H Kang G Watkins C Parr A Douglas-Jones R E Manseland W G Jiang ldquoStromal cell derived factor-1 its influence oninvasiveness and migration of breast cancer cells in vitro andits association with prognosis and survival in human breastcancerrdquo Breast Cancer Research vol 7 no 4 pp R402ndashR4102005

[97] Q D Chu L Panu N T Holm B D L Li L W Johnsonand S Zhang ldquoHigh chemokine receptor CXCR4 level intriple negative breast cancer specimens predicts poor clinical

Disease Markers 11

outcomerdquo Journal of Surgical Research vol 159 no 2 pp 689ndash695 2010

[98] H W Chen C W Du X L Wei U S Khoo and G J ZhangldquoCytoplasmic CXCR4 high-expression exhibits distinct poorclinicopathological characteristics and predicts poor prognosisin triple-negative breast cancerrdquo Current Molecular Medicinevol 13 no 3 pp 410ndash416 2013

[99] J-K Li L Yu Y Shen L-S Zhou Y-C Wang and J-HZhang ldquoInhibition of CXCR4 activity with AMD3100 decreasesinvasion of human colorectal cancer cells in vitrordquo WorldJournal of Gastroenterology vol 14 no 15 pp 2308ndash2313 2008

[100] K Christopherson II and R Hromas ldquoChemokine regulation ofnormal and pathologic immune responsesrdquo Stem Cells vol 19no 5 pp 388ndash396 2001

[101] C R Mackay ldquoChemokines immunologyrsquos high impact fac-torsrdquo Nature Immunology vol 2 no 2 pp 95ndash101 2001

[102] A Zlotnik O Yoshie and H Nomiyama ldquoThe chemokineand chemokine receptor superfamilies and their molecularevolutionrdquo Genome Biology vol 7 no 12 article 243 2006

[103] Y Zhang F Yao X Yao et al ldquoRole of CCL5 in invasionproliferation and proportion of CD44+CD24minus phenotype ofMCF-7 cells and correlation of CCL5 andCCR5 expressionwithbreast cancer progressionrdquo Oncology Reports vol 21 no 4 pp1113ndash1121 2009

[104] W B Fang I Jokar A Zou D Lambert P Dendukuri and NCheng ldquoCCL2CCR2 chemokine signaling coordinates survivaland motility of breast cancer cells through Smad3 protein- andp4244 mitogen-activated protein kinase (MAPK)-dependentmechanismsrdquo The Journal of Biological Chemistry vol 287 pp36593ndash36608 2012

[105] J L Steiner and E A Murphy ldquoImportance of chemokine (CC-motif) ligand 2 in breast cancerrdquo The International Journal ofBiological Markers vol 27 no 3 pp e179ndashe185 2012

[106] X Lu and Y Kang ldquoChemokine (C-C Motif) ligand 2 engagesCCR2+ stromal cells of monocytic origin to promote breastcancer metastasis to lung and bonerdquo The Journal of BiologicalChemistry vol 284 no 42 pp 29087ndash29096 2009

[107] T T Murooka R Rahbar and E N Fish ldquoCCL5 promotesproliferation of MCF-7 cells through mTOR-dependent mRNAtranslationrdquo Biochemical and Biophysical Research Communica-tions vol 387 no 2 pp 381ndash386 2009

[108] M Velasco-Velazquez and R G Pestell ldquoThe CCL5CCR5 axispromotes metastasis in basal breast cancerrdquo Oncoimmunologyvol 2 no 4 Article ID e23660 2013

[109] G Luboshits S Shina O Kaplan et al ldquoElevated expressionof the CC chemokine regulated on activation normal T cellexpressed and secreted (RANTES) in advanced breast carci-nomardquo Cancer Research vol 59 no 18 pp 4681ndash4687 1999

[110] M Cerna A Narsanska V Treska R Kucera and O TopolcanldquoIGF1 and tumor markers in different breast cancer stagesrdquoRozhledy v Chirurgii vol 90 no 12 pp 688ndash694 2011

[111] S Mezi L Todi E Orsi A Angeloni and P Mancini ldquoInvolve-ment of the Src-cortactin pathway inmigration induced by IGF-1 and EGF in human breast cancer cellsrdquo International Journalof Oncology vol 41 no 6 pp 2128ndash2138

[112] R Kucera M Cerna A Narsanska et al ldquoGrowth factorsand breast tumors comparison of selected growth factors withtraditional tumor markersrdquo Anticancer Research vol 31 no 12pp 4653ndash4656 2011

[113] H H Ahmed F MMetwally E S MahdyW G Shosha and SS Ramadan ldquoClinical value of serum hepatocyte growth factor

B-cell lymphoma-2 and nitric oxide in primary breast cancerpatientsrdquo European Review for Medical and PharmacologicalSciences vol 16 p 958 2012

[114] H Arias-Pulido N Chaher Y Gong C Qualls J Vargas andM Royce ldquoTumor stromal vascular endothelial growth factorA is predictive of poor outcome in inflammatory breast cancerrdquoBMC Cancer vol 12 p 298 2012

[115] J MM Oda K B de Oliveira R L Guembarovski KW A deLima A C D D Herrera A L Guembarovski et al ldquoTGF-120573 polymorphism and its expression correlated with CXCR4expression in human breast cancerrdquoMolecular Biology Reportsvol 39 no 12 pp 10131ndash10137 2012

[116] N Dumont and C L Arteaga ldquoTransforming growth factor-120573 and breast cancer tumor promoting effects of transforminggrowth factor-120573rdquo Breast Cancer Research vol 2 no 2 pp 125ndash132 2000

[117] S-M Sheen-Chen H-S Chen C-W Sheen H-L Eng andW-J Chen ldquoSerum levels of transforming growth factor 1205731 inpatients with breast cancerrdquo Archives of Surgery vol 136 no 8pp 937ndash940 2001

[118] J D Figueroa K C Flanders M Garcia-Closas et al ldquoExpres-sion of TGF-120573 signaling factors in invasive breast cancersrelationships with age at diagnosis and tumor characteristicsrdquoBreast Cancer Research and Treatment vol 121 no 3 pp 727ndash735 2010

[119] E M de Kruijf T J Dekker L J Hawinkels H Putter V TSmit J R Kroep et al ldquoThe prognostic role of TGF-120573 signalingpathway in breast cancer patientsrdquo Annals of Oncology vol 24no 2 pp 384ndash390 2013

[120] M Eilers and R N Eisenman ldquoMycrsquos broad reachrdquo Genes andDevelopment vol 22 no 20 pp 2755ndash2766 2008

[121] C V Dang ldquoc-Myc target genes involved in cell growthapoptosis andmetabolismrdquoMolecular and Cellular Biology vol19 no 1 pp 1ndash11 1999

[122] N Todorovic-Rakovic Z Neskovic-Konstantinovic and DNikolic-Vukosavljevic ldquoC-myc as a predictive marker forchemotherapy in metastatic breast cancerrdquo Clinical and Experi-mental Medicine vol 12 no 4 pp 217ndash223 2012

[123] A D Singhi A Cimino-Mathews R B Jenkins et al ldquoMYCgene amplification is often acquired in lethal distant breastcancer metastases of unamplified primary tumorsrdquo ModernPathology vol 25 no 3 pp 378ndash387 2012

[124] D Horiuchi L Kusdra N E Huskey S Chandriani ME Lenburg A M Gonzalez-Angulo et al ldquoMYC pathwayactivation in triple-negative breast cancer is synthetic lethalwith CDK inhibitionrdquo Journal of Experimental Medicine vol209 no 4 pp 679ndash696 2012

[125] J K Rummukainen T Salminen J Lundin S Kytola HJoensuu and J J Isola ldquoAmplification of c-myc by fluorescencein situ hybridization in a population-based breast cancer tissuearrayrdquoModern Pathology vol 14 no 10 pp 1030ndash1035 2001

[126] MOloomi S BouzariMAMohagheghi andHKhodayaran-Tehrani ldquoMolecular markers in peripheral blood of iranianwomen with breast cancerrdquo Cancer Microenviron vol 6 no 1pp 109ndash116 2013

[127] M Sahin E Sahin and S Koksoy ldquoRegulatory T cells in canceran overview and perspectives on cyclooxygenase-2 and Foxp3DNAmethylationrdquoHuman Immunology vol 74 no 9 pp 1061ndash1068 2013

[128] M A E Watanabe J M M Oda M K Amarante and J CesarVoltarelli ldquoRegulatory T cells and breast cancer implications

12 Disease Markers

for immunopathogenesisrdquo Cancer and Metastasis Reviews vol29 no 4 pp 569ndash579 2010

[129] L Wang R Liu W Li et al ldquoSomatic single hits inactivate theX-linked tumor suppressor FOXP3 in the prostaterdquoCancer Cellvol 16 no 4 pp 336ndash346 2009

[130] T Zuo R Liu H Zhang et al ldquoFOXP3 is a novel transcriptionalrepressor for the breast cancer oncogene SKP2rdquo The Journal ofClinical Investigation vol 117 no 12 pp 3765ndash3773 2007

[131] A Balsari A Merlo P Casalini et al ldquoFOXP3 expression andoverall survival in breast cancerrdquo Journal of Clinical Oncologyvol 27 no 11 pp 1746ndash1752 2009

[132] G-Y Chen C Chen L Wang X Chang P Zheng and Y LiuldquoCutting edge broad expression of the FoxP3 locus in epithelialcells a caution against early interpretation of fatal inflammatorydiseases following in vivo depletion of FoxP3-expressing cellsrdquoJournal of Immunology vol 180 no 8 pp 5163ndash5166 2008

[133] T Zuo L Wang C Morrison et al ldquoFOXP3 is an X-linkedbreast cancer suppressor gene and an important repressor ofthe HER-2ErbB2 oncogenerdquo Cell vol 129 no 7 pp 1275ndash12862007

[134] D Overbeck-Zubrzycka S Ali J Kirby and T LennardldquoFOXP3 transcription factor regulates metastatic spread ofbreast cancer via control of expression of CXCR4 chemokinereceptorrdquo British Journal of Surgery vol 98 no 1 pp 84ndash852011

[135] J RHarvey PMellorH Eldaly TW J Lennard J AKirby andS Ali ldquoInhibition of CXCR4-mediated breast cancermetastasisa potential role for heparinoidsrdquo Clinical Cancer Research vol13 no 5 pp 1562ndash1570 2007

[136] P Mellor J R Harvey K J Murphy et al ldquoModulatory effectsof heparin and short-length oligosaccharides of heparin on themetastasis and growth of LMDMDA-MB 231 breast cancer cellsin vivordquo British Journal of Cancer vol 97 no 6 pp 761ndash7682007

[137] M V Iorio M Ferracin C-G Liu et al ldquoMicroRNA geneexpression deregulation in human breast cancerrdquo CancerResearch vol 65 no 16 pp 7065ndash7070 2005

[138] S W Fu L Chen and Y G Man ldquomiRNA biomarkers in breastcancer detection andmanagementrdquo Journal of Cancer vol 2 pp116ndash122 2011

[139] D P Bartel ldquoMicroRNAs genomics biogenesis mechanismand functionrdquo Cell vol 116 no 2 pp 281ndash297 2004

[140] R I Gregory and R Shiekhattar ldquoMicroRNA biogenesis andcancerrdquo Cancer Research vol 65 no 9 pp 3509ndash3512 2005

[141] D D Taylor and C Gercel-Taylor ldquoMicroRNA signatures oftumor-derived exosomes as diagnostic biomarkers of ovariancancerrdquo Gynecologic Oncology vol 110 no 1 pp 13ndash21 2008

[142] L J Chin and F J Slack ldquoA truth serum for cancer microRNAshave major potential as cancer biomarkersrdquo Cell Research vol18 no 10 pp 983ndash984 2008

[143] P S Mitchell R K Parkin E M Kroh et al ldquoCirculatingmicroRNAs as stable blood-based markers for cancer detec-tionrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 105 no 30 pp 10513ndash10518 2008

[144] D P Bartel ldquoMicroRNAs target recognition and regulatoryfunctionsrdquo Cell vol 136 no 2 pp 215ndash233 2009

[145] D J Guarnieri and R J Dileone ldquoMicroRNAs a new class ofgene regulatorsrdquo Annals of Medicine vol 40 no 3 pp 197ndash2082008

[146] XWuG Somlo Y Yu et al ldquoDe novo sequencing of circulatingmiRNAs identifies novel markers predicting clinical outcome

of locally advanced breast cancerrdquo Journal of TranslationalMedicine vol 10 no 1 article 42 2012

[147] B Wang H Wang and Z Yang ldquoMiR-122 inhibits cell prolif-eration and tumorigenesis of breast cancer by targeting IGF1RrdquoPloS ONE vol 7 no 10 Article ID e47053 2012

[148] L Shen J Li L Xu et al ldquomiR-497 induces apoptosis of breastcancer cells by targeting Bcl-wrdquo Experimental and TherapeuticMedicine vol 3 no 3 pp 475ndash480 2012

[149] C M Croce ldquoCauses and consequences of microRNA dysreg-ulation in cancerrdquo Nature Reviews Genetics vol 10 no 10 pp704ndash714 2009

[150] Q Huang K Gumireddy M Schrier et al ldquoThe microRNAsmiR-373 and miR-520c promote tumour invasion and metasta-sisrdquo Nature Cell Biology vol 10 no 2 pp 202ndash210 2008

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawi Publishing Corporation httpwwwhindawicom Volume 2013

The Scientific World Journal

International Journal of

EndocrinologyHindawi Publishing Corporationhttpwwwhindawicom

Volume 2013

ISRN Anesthesiology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

PPARRe sea rch

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

ISRN AIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

BioMed Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

ISRN Addiction

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Computational and Mathematical Methods in Medicine

ISRN Allergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Journal of

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Evidence-Based Complementary and Alternative Medicine

Volume 2013Hindawi Publishing Corporationhttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

ISRN Biomarkers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

MEDIATORSINFLAMMATION

of

Disease Markers 11

outcomerdquo Journal of Surgical Research vol 159 no 2 pp 689ndash695 2010

[98] H W Chen C W Du X L Wei U S Khoo and G J ZhangldquoCytoplasmic CXCR4 high-expression exhibits distinct poorclinicopathological characteristics and predicts poor prognosisin triple-negative breast cancerrdquo Current Molecular Medicinevol 13 no 3 pp 410ndash416 2013

[99] J-K Li L Yu Y Shen L-S Zhou Y-C Wang and J-HZhang ldquoInhibition of CXCR4 activity with AMD3100 decreasesinvasion of human colorectal cancer cells in vitrordquo WorldJournal of Gastroenterology vol 14 no 15 pp 2308ndash2313 2008

[100] K Christopherson II and R Hromas ldquoChemokine regulation ofnormal and pathologic immune responsesrdquo Stem Cells vol 19no 5 pp 388ndash396 2001

[101] C R Mackay ldquoChemokines immunologyrsquos high impact fac-torsrdquo Nature Immunology vol 2 no 2 pp 95ndash101 2001

[102] A Zlotnik O Yoshie and H Nomiyama ldquoThe chemokineand chemokine receptor superfamilies and their molecularevolutionrdquo Genome Biology vol 7 no 12 article 243 2006

[103] Y Zhang F Yao X Yao et al ldquoRole of CCL5 in invasionproliferation and proportion of CD44+CD24minus phenotype ofMCF-7 cells and correlation of CCL5 andCCR5 expressionwithbreast cancer progressionrdquo Oncology Reports vol 21 no 4 pp1113ndash1121 2009

[104] W B Fang I Jokar A Zou D Lambert P Dendukuri and NCheng ldquoCCL2CCR2 chemokine signaling coordinates survivaland motility of breast cancer cells through Smad3 protein- andp4244 mitogen-activated protein kinase (MAPK)-dependentmechanismsrdquo The Journal of Biological Chemistry vol 287 pp36593ndash36608 2012

[105] J L Steiner and E A Murphy ldquoImportance of chemokine (CC-motif) ligand 2 in breast cancerrdquo The International Journal ofBiological Markers vol 27 no 3 pp e179ndashe185 2012

[106] X Lu and Y Kang ldquoChemokine (C-C Motif) ligand 2 engagesCCR2+ stromal cells of monocytic origin to promote breastcancer metastasis to lung and bonerdquo The Journal of BiologicalChemistry vol 284 no 42 pp 29087ndash29096 2009

[107] T T Murooka R Rahbar and E N Fish ldquoCCL5 promotesproliferation of MCF-7 cells through mTOR-dependent mRNAtranslationrdquo Biochemical and Biophysical Research Communica-tions vol 387 no 2 pp 381ndash386 2009

[108] M Velasco-Velazquez and R G Pestell ldquoThe CCL5CCR5 axispromotes metastasis in basal breast cancerrdquo Oncoimmunologyvol 2 no 4 Article ID e23660 2013

[109] G Luboshits S Shina O Kaplan et al ldquoElevated expressionof the CC chemokine regulated on activation normal T cellexpressed and secreted (RANTES) in advanced breast carci-nomardquo Cancer Research vol 59 no 18 pp 4681ndash4687 1999

[110] M Cerna A Narsanska V Treska R Kucera and O TopolcanldquoIGF1 and tumor markers in different breast cancer stagesrdquoRozhledy v Chirurgii vol 90 no 12 pp 688ndash694 2011

[111] S Mezi L Todi E Orsi A Angeloni and P Mancini ldquoInvolve-ment of the Src-cortactin pathway inmigration induced by IGF-1 and EGF in human breast cancer cellsrdquo International Journalof Oncology vol 41 no 6 pp 2128ndash2138

[112] R Kucera M Cerna A Narsanska et al ldquoGrowth factorsand breast tumors comparison of selected growth factors withtraditional tumor markersrdquo Anticancer Research vol 31 no 12pp 4653ndash4656 2011

[113] H H Ahmed F MMetwally E S MahdyW G Shosha and SS Ramadan ldquoClinical value of serum hepatocyte growth factor

B-cell lymphoma-2 and nitric oxide in primary breast cancerpatientsrdquo European Review for Medical and PharmacologicalSciences vol 16 p 958 2012

[114] H Arias-Pulido N Chaher Y Gong C Qualls J Vargas andM Royce ldquoTumor stromal vascular endothelial growth factorA is predictive of poor outcome in inflammatory breast cancerrdquoBMC Cancer vol 12 p 298 2012

[115] J MM Oda K B de Oliveira R L Guembarovski KW A deLima A C D D Herrera A L Guembarovski et al ldquoTGF-120573 polymorphism and its expression correlated with CXCR4expression in human breast cancerrdquoMolecular Biology Reportsvol 39 no 12 pp 10131ndash10137 2012

[116] N Dumont and C L Arteaga ldquoTransforming growth factor-120573 and breast cancer tumor promoting effects of transforminggrowth factor-120573rdquo Breast Cancer Research vol 2 no 2 pp 125ndash132 2000

[117] S-M Sheen-Chen H-S Chen C-W Sheen H-L Eng andW-J Chen ldquoSerum levels of transforming growth factor 1205731 inpatients with breast cancerrdquo Archives of Surgery vol 136 no 8pp 937ndash940 2001

[118] J D Figueroa K C Flanders M Garcia-Closas et al ldquoExpres-sion of TGF-120573 signaling factors in invasive breast cancersrelationships with age at diagnosis and tumor characteristicsrdquoBreast Cancer Research and Treatment vol 121 no 3 pp 727ndash735 2010

[119] E M de Kruijf T J Dekker L J Hawinkels H Putter V TSmit J R Kroep et al ldquoThe prognostic role of TGF-120573 signalingpathway in breast cancer patientsrdquo Annals of Oncology vol 24no 2 pp 384ndash390 2013

[120] M Eilers and R N Eisenman ldquoMycrsquos broad reachrdquo Genes andDevelopment vol 22 no 20 pp 2755ndash2766 2008

[121] C V Dang ldquoc-Myc target genes involved in cell growthapoptosis andmetabolismrdquoMolecular and Cellular Biology vol19 no 1 pp 1ndash11 1999

[122] N Todorovic-Rakovic Z Neskovic-Konstantinovic and DNikolic-Vukosavljevic ldquoC-myc as a predictive marker forchemotherapy in metastatic breast cancerrdquo Clinical and Experi-mental Medicine vol 12 no 4 pp 217ndash223 2012

[123] A D Singhi A Cimino-Mathews R B Jenkins et al ldquoMYCgene amplification is often acquired in lethal distant breastcancer metastases of unamplified primary tumorsrdquo ModernPathology vol 25 no 3 pp 378ndash387 2012

[124] D Horiuchi L Kusdra N E Huskey S Chandriani ME Lenburg A M Gonzalez-Angulo et al ldquoMYC pathwayactivation in triple-negative breast cancer is synthetic lethalwith CDK inhibitionrdquo Journal of Experimental Medicine vol209 no 4 pp 679ndash696 2012

[125] J K Rummukainen T Salminen J Lundin S Kytola HJoensuu and J J Isola ldquoAmplification of c-myc by fluorescencein situ hybridization in a population-based breast cancer tissuearrayrdquoModern Pathology vol 14 no 10 pp 1030ndash1035 2001

[126] MOloomi S BouzariMAMohagheghi andHKhodayaran-Tehrani ldquoMolecular markers in peripheral blood of iranianwomen with breast cancerrdquo Cancer Microenviron vol 6 no 1pp 109ndash116 2013

[127] M Sahin E Sahin and S Koksoy ldquoRegulatory T cells in canceran overview and perspectives on cyclooxygenase-2 and Foxp3DNAmethylationrdquoHuman Immunology vol 74 no 9 pp 1061ndash1068 2013

[128] M A E Watanabe J M M Oda M K Amarante and J CesarVoltarelli ldquoRegulatory T cells and breast cancer implications

12 Disease Markers

for immunopathogenesisrdquo Cancer and Metastasis Reviews vol29 no 4 pp 569ndash579 2010

[129] L Wang R Liu W Li et al ldquoSomatic single hits inactivate theX-linked tumor suppressor FOXP3 in the prostaterdquoCancer Cellvol 16 no 4 pp 336ndash346 2009

[130] T Zuo R Liu H Zhang et al ldquoFOXP3 is a novel transcriptionalrepressor for the breast cancer oncogene SKP2rdquo The Journal ofClinical Investigation vol 117 no 12 pp 3765ndash3773 2007

[131] A Balsari A Merlo P Casalini et al ldquoFOXP3 expression andoverall survival in breast cancerrdquo Journal of Clinical Oncologyvol 27 no 11 pp 1746ndash1752 2009

[132] G-Y Chen C Chen L Wang X Chang P Zheng and Y LiuldquoCutting edge broad expression of the FoxP3 locus in epithelialcells a caution against early interpretation of fatal inflammatorydiseases following in vivo depletion of FoxP3-expressing cellsrdquoJournal of Immunology vol 180 no 8 pp 5163ndash5166 2008

[133] T Zuo L Wang C Morrison et al ldquoFOXP3 is an X-linkedbreast cancer suppressor gene and an important repressor ofthe HER-2ErbB2 oncogenerdquo Cell vol 129 no 7 pp 1275ndash12862007

[134] D Overbeck-Zubrzycka S Ali J Kirby and T LennardldquoFOXP3 transcription factor regulates metastatic spread ofbreast cancer via control of expression of CXCR4 chemokinereceptorrdquo British Journal of Surgery vol 98 no 1 pp 84ndash852011

[135] J RHarvey PMellorH Eldaly TW J Lennard J AKirby andS Ali ldquoInhibition of CXCR4-mediated breast cancermetastasisa potential role for heparinoidsrdquo Clinical Cancer Research vol13 no 5 pp 1562ndash1570 2007

[136] P Mellor J R Harvey K J Murphy et al ldquoModulatory effectsof heparin and short-length oligosaccharides of heparin on themetastasis and growth of LMDMDA-MB 231 breast cancer cellsin vivordquo British Journal of Cancer vol 97 no 6 pp 761ndash7682007

[137] M V Iorio M Ferracin C-G Liu et al ldquoMicroRNA geneexpression deregulation in human breast cancerrdquo CancerResearch vol 65 no 16 pp 7065ndash7070 2005

[138] S W Fu L Chen and Y G Man ldquomiRNA biomarkers in breastcancer detection andmanagementrdquo Journal of Cancer vol 2 pp116ndash122 2011

[139] D P Bartel ldquoMicroRNAs genomics biogenesis mechanismand functionrdquo Cell vol 116 no 2 pp 281ndash297 2004

[140] R I Gregory and R Shiekhattar ldquoMicroRNA biogenesis andcancerrdquo Cancer Research vol 65 no 9 pp 3509ndash3512 2005

[141] D D Taylor and C Gercel-Taylor ldquoMicroRNA signatures oftumor-derived exosomes as diagnostic biomarkers of ovariancancerrdquo Gynecologic Oncology vol 110 no 1 pp 13ndash21 2008

[142] L J Chin and F J Slack ldquoA truth serum for cancer microRNAshave major potential as cancer biomarkersrdquo Cell Research vol18 no 10 pp 983ndash984 2008

[143] P S Mitchell R K Parkin E M Kroh et al ldquoCirculatingmicroRNAs as stable blood-based markers for cancer detec-tionrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 105 no 30 pp 10513ndash10518 2008

[144] D P Bartel ldquoMicroRNAs target recognition and regulatoryfunctionsrdquo Cell vol 136 no 2 pp 215ndash233 2009

[145] D J Guarnieri and R J Dileone ldquoMicroRNAs a new class ofgene regulatorsrdquo Annals of Medicine vol 40 no 3 pp 197ndash2082008

[146] XWuG Somlo Y Yu et al ldquoDe novo sequencing of circulatingmiRNAs identifies novel markers predicting clinical outcome

of locally advanced breast cancerrdquo Journal of TranslationalMedicine vol 10 no 1 article 42 2012

[147] B Wang H Wang and Z Yang ldquoMiR-122 inhibits cell prolif-eration and tumorigenesis of breast cancer by targeting IGF1RrdquoPloS ONE vol 7 no 10 Article ID e47053 2012

[148] L Shen J Li L Xu et al ldquomiR-497 induces apoptosis of breastcancer cells by targeting Bcl-wrdquo Experimental and TherapeuticMedicine vol 3 no 3 pp 475ndash480 2012

[149] C M Croce ldquoCauses and consequences of microRNA dysreg-ulation in cancerrdquo Nature Reviews Genetics vol 10 no 10 pp704ndash714 2009

[150] Q Huang K Gumireddy M Schrier et al ldquoThe microRNAsmiR-373 and miR-520c promote tumour invasion and metasta-sisrdquo Nature Cell Biology vol 10 no 2 pp 202ndash210 2008

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawi Publishing Corporation httpwwwhindawicom Volume 2013

The Scientific World Journal

International Journal of

EndocrinologyHindawi Publishing Corporationhttpwwwhindawicom

Volume 2013

ISRN Anesthesiology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

PPARRe sea rch

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

ISRN AIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

BioMed Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

ISRN Addiction

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Computational and Mathematical Methods in Medicine

ISRN Allergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Journal of

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Evidence-Based Complementary and Alternative Medicine

Volume 2013Hindawi Publishing Corporationhttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

ISRN Biomarkers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

MEDIATORSINFLAMMATION

of

12 Disease Markers

for immunopathogenesisrdquo Cancer and Metastasis Reviews vol29 no 4 pp 569ndash579 2010

[129] L Wang R Liu W Li et al ldquoSomatic single hits inactivate theX-linked tumor suppressor FOXP3 in the prostaterdquoCancer Cellvol 16 no 4 pp 336ndash346 2009

[130] T Zuo R Liu H Zhang et al ldquoFOXP3 is a novel transcriptionalrepressor for the breast cancer oncogene SKP2rdquo The Journal ofClinical Investigation vol 117 no 12 pp 3765ndash3773 2007

[131] A Balsari A Merlo P Casalini et al ldquoFOXP3 expression andoverall survival in breast cancerrdquo Journal of Clinical Oncologyvol 27 no 11 pp 1746ndash1752 2009

[132] G-Y Chen C Chen L Wang X Chang P Zheng and Y LiuldquoCutting edge broad expression of the FoxP3 locus in epithelialcells a caution against early interpretation of fatal inflammatorydiseases following in vivo depletion of FoxP3-expressing cellsrdquoJournal of Immunology vol 180 no 8 pp 5163ndash5166 2008

[133] T Zuo L Wang C Morrison et al ldquoFOXP3 is an X-linkedbreast cancer suppressor gene and an important repressor ofthe HER-2ErbB2 oncogenerdquo Cell vol 129 no 7 pp 1275ndash12862007

[134] D Overbeck-Zubrzycka S Ali J Kirby and T LennardldquoFOXP3 transcription factor regulates metastatic spread ofbreast cancer via control of expression of CXCR4 chemokinereceptorrdquo British Journal of Surgery vol 98 no 1 pp 84ndash852011

[135] J RHarvey PMellorH Eldaly TW J Lennard J AKirby andS Ali ldquoInhibition of CXCR4-mediated breast cancermetastasisa potential role for heparinoidsrdquo Clinical Cancer Research vol13 no 5 pp 1562ndash1570 2007

[136] P Mellor J R Harvey K J Murphy et al ldquoModulatory effectsof heparin and short-length oligosaccharides of heparin on themetastasis and growth of LMDMDA-MB 231 breast cancer cellsin vivordquo British Journal of Cancer vol 97 no 6 pp 761ndash7682007

[137] M V Iorio M Ferracin C-G Liu et al ldquoMicroRNA geneexpression deregulation in human breast cancerrdquo CancerResearch vol 65 no 16 pp 7065ndash7070 2005

[138] S W Fu L Chen and Y G Man ldquomiRNA biomarkers in breastcancer detection andmanagementrdquo Journal of Cancer vol 2 pp116ndash122 2011

[139] D P Bartel ldquoMicroRNAs genomics biogenesis mechanismand functionrdquo Cell vol 116 no 2 pp 281ndash297 2004

[140] R I Gregory and R Shiekhattar ldquoMicroRNA biogenesis andcancerrdquo Cancer Research vol 65 no 9 pp 3509ndash3512 2005

[141] D D Taylor and C Gercel-Taylor ldquoMicroRNA signatures oftumor-derived exosomes as diagnostic biomarkers of ovariancancerrdquo Gynecologic Oncology vol 110 no 1 pp 13ndash21 2008

[142] L J Chin and F J Slack ldquoA truth serum for cancer microRNAshave major potential as cancer biomarkersrdquo Cell Research vol18 no 10 pp 983ndash984 2008

[143] P S Mitchell R K Parkin E M Kroh et al ldquoCirculatingmicroRNAs as stable blood-based markers for cancer detec-tionrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 105 no 30 pp 10513ndash10518 2008

[144] D P Bartel ldquoMicroRNAs target recognition and regulatoryfunctionsrdquo Cell vol 136 no 2 pp 215ndash233 2009

[145] D J Guarnieri and R J Dileone ldquoMicroRNAs a new class ofgene regulatorsrdquo Annals of Medicine vol 40 no 3 pp 197ndash2082008

[146] XWuG Somlo Y Yu et al ldquoDe novo sequencing of circulatingmiRNAs identifies novel markers predicting clinical outcome

of locally advanced breast cancerrdquo Journal of TranslationalMedicine vol 10 no 1 article 42 2012

[147] B Wang H Wang and Z Yang ldquoMiR-122 inhibits cell prolif-eration and tumorigenesis of breast cancer by targeting IGF1RrdquoPloS ONE vol 7 no 10 Article ID e47053 2012

[148] L Shen J Li L Xu et al ldquomiR-497 induces apoptosis of breastcancer cells by targeting Bcl-wrdquo Experimental and TherapeuticMedicine vol 3 no 3 pp 475ndash480 2012

[149] C M Croce ldquoCauses and consequences of microRNA dysreg-ulation in cancerrdquo Nature Reviews Genetics vol 10 no 10 pp704ndash714 2009

[150] Q Huang K Gumireddy M Schrier et al ldquoThe microRNAsmiR-373 and miR-520c promote tumour invasion and metasta-sisrdquo Nature Cell Biology vol 10 no 2 pp 202ndash210 2008

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawi Publishing Corporation httpwwwhindawicom Volume 2013

The Scientific World Journal

International Journal of

EndocrinologyHindawi Publishing Corporationhttpwwwhindawicom

Volume 2013

ISRN Anesthesiology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

PPARRe sea rch

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

ISRN AIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

BioMed Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

ISRN Addiction

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Computational and Mathematical Methods in Medicine

ISRN Allergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Journal of

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Evidence-Based Complementary and Alternative Medicine

Volume 2013Hindawi Publishing Corporationhttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

ISRN Biomarkers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

MEDIATORSINFLAMMATION

of

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawi Publishing Corporation httpwwwhindawicom Volume 2013

The Scientific World Journal

International Journal of

EndocrinologyHindawi Publishing Corporationhttpwwwhindawicom

Volume 2013

ISRN Anesthesiology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

PPARRe sea rch

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

ISRN AIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

BioMed Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

ISRN Addiction

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Computational and Mathematical Methods in Medicine

ISRN Allergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Journal of

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Evidence-Based Complementary and Alternative Medicine

Volume 2013Hindawi Publishing Corporationhttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

ISRN Biomarkers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

MEDIATORSINFLAMMATION

of