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The Significance of CXCR4 Expression for the Prediction of Lymph Node Metastasis in Breast Cancer Patients

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The Significance of CXCR4 Expression for the Prediction of Lymph Node Metastasis in Breast Cancer Patientsof,The,CXCR4,for,the,Lymph,Node,lymph,node,cxcr4

The Significance of CXCR4 Expression for

    the Prediction of Lymph Node Metastasis in

    Breast Cancer Patients ChinJChOncol(20081S:83.86

    DO1lO.1O07/sll805.008.0083.6

    ?

    TheSignificanceofCXCR4ExpressionforthePredictionof

    LymphNodeMetastasisinBreastCancerPatients YongxingDing

    ChenghuaLi1

    Qinglingrang~

    Chang]ieChen

    ZenongCheng2

    'DepartmentofSurgicalOncology,Bengbu CentralHospital,Bengbu233000,Anhuiprov

    ince.China.

    DepartmentofBiochemistry&Molecular BiologyandPathology,BengbuMedicalCol

    lege,Bengbu233000,Anhuiprovince,China. Correspondenceto:YongxingDing

    E-mail:yqlmimi@163.com

    Thisworkwassupportedbygrantsfr0mthe AnhuiprovinciaINaturaIScienceFoundation (No.070413119).lheAnhuiprovinciaIpro. gramforAppliedTechnologyofClinicalMedi

    cinefNo.06B1051andlheBengbuScientific

PlanningPr~ectfNo.200617).

    ReceivedSeptember9,2007;acceptedJanu-

    ary17.2008.

    CJCOhttp://www.cjco.cB

    E-mail:cocr@eyou.corn

    Tel(Fax):86-22-23522919

    OBJECTIVEThechemokinereceptor(CXCI)CXCchemokine

    receptor4,playsanimportantroleincancermetastasis.We thereforestudieddifferentialexpressionoftheCXCR4,aswell asthatofthebiomarkerHER2,soastoevaluatewhetherthese biomarkerscanbeusedtopredictaxillarylymphnodemetastasis inbreastcancerpatients.

    METH0DSImmunohistochemistrywasusedtoevaluate theCXCR4andHER2expressionsandtoexaminetheparaffin sectionsofthebreastcancersatvariousstages.Positivelymph nodeexpressionwasfoundin80ofthecases,andin7therewas negativeexpression.

    RESUITSComparedtothecaseswithnegativelymphnodes, therewasahighexpressionofCXCI(26.3%s.14.3%,P=0.013),

    andanover.expressionofHER2(28.8%s.14.3%,P=0.011).

    Moreover,therewasadirectcorrelationbetweentheCXCIand HER2expressionsandthetumorstaging(P=0.000)andlymph nodemetastasisfP=0.032).Whenthetwobiomarkers,i.e.CXCR4 andHER2,wereconcurrentlVlabeled,ahighexpressionofone ofthebiomarkerscouldbeseeninthecaseswithpositivelymph nodes(51.3%s.28.6%,P<0.003).

    C0NCLUS10NThechemokinereceptor,CXCR4,isanewtype

    biomarkerinpredictingaxillarylymph.nodemetastasisinbreast cancers.Comparedwiththeothermarkers,suchasHER2etc., assessmentofCXCR4canimprovethepredictionofthepresence

andextentoflvmphnodeinvolvement.

    KEYWORDS:breastcance~immunohistochemicalstaining,tu- morstage,lymphnodestatus.

    Copyright2008ChineseAn~CancerAssociation

    Introduction

    Severalunverifiedbiomarkershave

    tialoflymphnodemetastasis[",in

    beenusedtoevaluatethepoten

    ordertoavoidclearingofaxil

    larynodesincaseswithearlystage(Stage.T11breastcancer.For example.HER2isawel1.knownbiomarkerrelatedtobreastcancer metastasis.However.thevalueOfHER2over-expressionisquestion

    ableinpredictingthepresenceoflymphnodemetastasis[2,3].Recent studieshaveshownthatinbreastcancers,theinteractionbetweena chemokinereceptoranditsligandinhostorgansmayplayarolein themetastasisofmalignanttumorsH,5.Thereisahighexpressionof

    thechemokinereceptorCXCchemokinereceptor4(CXCR4)inthe primaryfoCUSwithmetastaticbreastcancer,andahighexpressionof theCXCR4'sligand.SDF.1inliver,bonemalTOlungandlymph nodes.Inourstudy,therefore.theexpressionofCXCR4andHER2 inbreastcancerpatientswithpositiveandnegativelymphnodeswas investigated.inordertoevaluatethepotentialofthesemarkersin predictingaxillarynodemetastaticinvolvement.

    Springer

ChinJClinOncol(2008)5:83-86

    MaterialsandMethods

    Generaldata

    A11specimensfromthe87breastcancerpatientsinour groupwerecollectedfromthecasesinourhospitals.i.e.

theBengbuCentra1Hospita1.ortheAliatedHospital

    ofBengbuMedica1College.duringaperiodfromJanu

    ary2001toDecember2006.WH0pathologicaltyping wasusedtoclassifythecases.whichincludedthefo1

    1owingcarcinomas:infitratingductal,medullary,intra

    ducta1andinfiltrating1obular.BasedontheUICCTNM staging.StageItoIIdiseaseswerefc)undin52cases, andStageIIItoIVin35.Therewere80caseswhich were1ymphnodepositive,and7lymphnodenegative. Lymphnodeclearancewasconductedinal1thepatients. andevaluationperfonnedbyroutineH&Estaining.A11 patientswerefemale.withameanageOf43.3years. Datafromal1caseswereretrospective.

    Reagen~andMethods

    TheSABCmethodfromthehanBosterBioengi

    neefingCo.wasusedtoassesstheimmunohistochemi

    ca1stainsexpressedbytheCXCR4protein.Thefirst antibodywasmouse.antihumanCXCR4(R&DCo.1. TheSPmethodfromtheFuzhouMaiXinBiotechnol

    ogyDevelopmentCo.Ltd.wasusedtoassesstheHER2 protein.employingMBIMAB0918mouseantiHER2

    asthefirstantibody.

    Methods

    Histologica1sectionswithestablishedpositiveresults wereusedaspositivecontrolsintheimmunohistochem

    ica1(ICH)staining.andPBSwasusedtoreplacethe firstantibodyinnegativecontrols.Thepositivecriterion ofHER2wasbasedonformationofabrownishyellow

    coloronthecellularmembranefCM1.Ascoreof0+was definedasnomembranestainingorbarelyperceptible

    membranestainingin1essthan10%ofcells.ascoreof 1+wasdefinedasbarelyperceptiblemembranestaining inmorethan10%ofthecells,ascoreof2+wasdefined asweak-?to-?moderatecompletemembranestainingpres-? entinmorethan10%ofthetumorcells.andascoreof 3+wasdefinedasstrongcompletemembranestainingin morethanl0%ofthetumorcells.TheHER2couldbe deemedaspositiveiftheCMofmorethan10%ofthe tumorcellswasstained.

    CXCR4wasconsideredpositivecells,iftheCMor cytoplasmpresentedabrownishyellowcolor.TheICH

    stainingofthesectionswasclassifiedas1ow,moderate orstrongstainingbasedonthebackground.Appraise

    mentofthepositivecel1percentagewasbasedonaratio ofthepositivetumorcel1counttothetota1tumorcel1 count.Atthesametime,nuclearstainingofthespeci

    menwasobserved.

    Statisticalaria~sis

    SPSS10.1softwarewasusedforstatistica1analysis.Ab

    solutevariablesweredeterminedusingtheZ2testwith thevalueOf<0.05setasastatistica1significance. Multifactoria11inearregressionanalysiswasusedfor healthriskfactorappraisement.

    Results

    cXcR4expressioninbreastcancers

    APEARMANcorrelationanalysisshowedthattherewas apositivecorrelationbetweenCXCR4expressionand theTNMbreastcancerstagingaswel1aswithlymph nodemetastasis.Thepositiveratewas24.6%f14/571 incaseswith1essthan3lymphnodemetastases.and

    53-3%f16/30)incaseswithmorethan3lymphnode metastases,showingastatisticalsignificancebetween thetwogroupsrP=0.032).Thepositiveratesofthe TNMStageItoIIandtheStageIIItOIVcancerswere

    respectively10.5%and77.1%fP=0.000).Therewas nosignificantcorrelationwithpatient'sagerP=0.453) andtheirmensesstatusfP=0.785).Inaddition,there wasapositivecorrelationbetweenCXCR4expression andtheHER2=0.0151biomarker(Table1).

    Correlationfactorsrelatinglymphnodemetastasis Comparedtocancertissuesassociatedwithposi

    tive1ymphnodes.highcytoplasmicstainingofthe CXCR4(26-3%vs.14-3%,P=0.0131andHER2over- expression(28.8%vs.14-3%P=0.01l1werepresentif therewerepositivelymphnodes.Ahighexpressionof CXCR4wasfoundin32.2%ofthecancerswithpositive 1ymphnodes.andonly12.5%ofthecancerswithnega

    Table1.RelationshipbetweenCXCR4expressionandclinic0path0l0gicparametersofthebr

    eastcancers.

    Springer

JClin0ncol(2008)5:83.86

    tive1ymphnodes.Whenthetwobiomarkersfcytoplas- micCXCR4andHER2)wereconcurrentlyutilizedei- therCXCR4orHER2expressionwasapparentin51_3% ofthecancercaseswithmetastases.Comparedtothe assessmentofonlyonebiomarker,detectionsensitiv- itywasenhanced(cytoplasmicCXCR4positive26.3%. HER2positive28.8%1bytheuseofthetwobiomarkers.

    Therefore,thedetectionrateoflymphnodemetastasis wasenhancedbyconcurrentemploymentofthetwo biomarkers(Table2andFig.11.

    Discussion

    Lymphnodemetastasesareatpresent,stillthemajor referenceindexforthejudgmentofbreastcancerprog- nosisandmakingatreatmentplan.However,thereisno detectionindexcompletelysuitableforroutineclinical application.Currentlythemechanismoftumorcellu- 1arinfiltrationandproductionoflymphnodesremains unclear.Previousstudies[6haveshownthatthereisan

    expressionofthechemokinereceptorCXCR4insevera1 immunecells.andthattheCXC:R4anditsCXCL12 1igandwil1playamajorroleintumor-cel1homingto 1ymphnodesororgans.Ithasbeenfoundinrecentstud- ies[7.9thatCXCR4alsoisexpressedinthemalignant tumorcells.anditmaybeinvolvedinlymphaticmetas- tasisandbreastcancerprogression.

    Inourstudy,thebiologicalsignificanceofCXCR4 expressioninbreastcancers,withorwithoutlymph nodemetastasis,wasanalyzedtoinvestigatewhether CXCR4expressioncouldbeusedinpredictingtheper- centageandscopeofaxillarylymphnodemetastasis. OurfindingsindicatedthatpositiveCXCR4cytoplasmic stainingandHER2over.exDressionaresignificantbio- markerstosuggestthepresenceoflymphnodemetasta- sis.Moreover,theco.expressionofCXCR4andHER2 Table2.Analysisofthecorrelationfactorswithlymphnodemetastases.

    }

    ,

HighCXCR4expressionwasconfirmedwhenstrongpositivestainingwaspresentinmoreth

    an30%ofthe

    cells.ormoderatestainingpresentinmorethan50%oftumorcells;,HER2positivitywasconfi

    rmedascom

    pleteorstrongpositivecytoplasmicstainingwhenpresentinmorethan10%ofthetumorcells-

    Fig.1.TheexpressionofCXCR4andHER2inbreastcancer(DABcoloration,~1oo)-A,Nega

    tiveexpression

    OfCXCR4;B,LowexpressionofCXCR4;C,Over

    expressionofCXCR4,andD,Over-expressionofHER2,

    amongwhichtherewasinCandDthesamespecimenfromthecasewithmorethanthreelymphnodememsmses?

    Springer

JClmOucol(2008)S:83-86

    isamoresensitiveindexoflymphnodeinfiltrationthan

    asinglebiomarker.

    In2003areport[10]confirmedthattheSDF.10/CXCR4

    signalingaxiscanplayadefiniteroleinlymphnodeme-

    tastasisofcancers.StudiesconductedbyBladeseta1.

    demonstratedthattheinductionofSDF.1a/CXCR4

    mayallowtheinvasionoflymphoidtissuebyperiph.

    eralleukocytesviathebloodcirculation.Tamamura

    etaI.ffoundthattheantagonistTl40ofCXCR4can

    inhibittheinvitrotransmigrationofthebreastcancer

    MDA.MB.23lcells.andinananimalmodelofhuman

    breastcancer-bearingmice,itcanreducetheoccurrence ofmetastasistothelung.Tosummarizetheabove,an

    increaseoftheCXCR4expressioninaprimarytumor

    mayindicatethestateoflymphnodemetastasisandthat

    highCXCR4expressionindicatesmoreextensivelymph

nodemetastasis.

    TheHER2cancergeneisamemberofthegrowth

    factorreceptor.Ifamily.HER2enhancesCXCR4ex. pression,i.e.,ononehand,HER2acceptsthesignals ofanextracellulardomain.andstimulatescellgrowth throughthetyrosinekinasepathway;ontheother, HER2enhancesbreastcancercellmetastasisbystimu. 1atingCXCR4expression.Itwasfoundinourstudies thattherewasacorrelationbetweenover.expressionof HER.2andanonfavorableprognosis.Ithasbeendem. onstrated[13]thatremissionandsurvivalratesofbreast cancerpatientswithanover--expressionoftheHER..2 werebothunfavorable.Ourresultsalsoshowedthat HER2over.expressioncorrelatedwithaxillarylymph nodemetastasis.Currentlybiotherapytargetingatthe HER2/neugene(i.e.c-erbB2gene)siteisarecentworld. widemodeoftreatment.Herceptin,anewdrugdeve1. opedintheUShasbeenapprovedbytheFDA.Thisis thefirstclinicallyappliedhumananti..HER2/neumono.. clonalantibodv4_.

    Althoughwehavereportedthecorrelationandhigh specificityoftheCXCR4andHER2biomarkersin lymphnodeinfiltration.asanindependentfactor,over- expressionoftheHER2/neugenewasfoundinonly 20%-30%ofthebreastcancerpatientsThecombined assessmentofCXCR4andHER2expressionmaypre. dicthalfofthelymphnodemetastasis,thusconsiderably improvingthesensitivityofdetections.

    Inshort,ourdatahaveshownthatthechemokinere. ceptorCXCR4isanew.typemarkerforbreastcancer

    lymphnodemetastasis.Itcanbehelpfultopredictthe possibilityoflymphnodemetastasis,andwithHER2 relatetothelymphnodestatetodirectthemodeofsur. gery,treatmentplananddevelopaprognosis.Specific antagonistsareexpectedtobeemployedtotargetma- lignanttumors.EmergenceofthenewHER2/neumono. Springer

    clonalantibodytreatmentbringshopeforbreastcancer patients.

    2

    TaOJ.YouL.WangXS.RelationshiPbetweentheIabels oftumorCEA.CA153andclinicaIdiagnosisofbreast cancer.ChinJCIinOncoI2005:32:3134(Chinese).

    AnanK,MorisakiT,KatanoM.etaI.Assessmentof cerbB2andvascuIarendotheliaIgrowthfactormRNA expressioninfine-needleaspirtesfrOmearlybreast carcinomas:preoperative

    potentia1.EurJSurgOnco

    determinationofmalignant

    1998:24:2833.

    3SchneiderJ,PollanM,TejerinaA,eta1.ACCUmulation OfuPAPAIlcomplexesinsidethetumorcellsisas

    sociatedwithaxan/nodaIinvasioninprogesterone

    receptorpositiveearlybreastcancer.BrJCancer2003: 88:96101.

    4LeeBC,LeeTH,AvrahamS,etaI.Involvementofthe chemokinereceptorCXCR4anditsIigandstromaI cellderivedfactor1ocinbreastcancereelImigration throughhumanbrainmicrOvascuIarendotheliaIcells.

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