Coexpression of steroid hormone receptors estrogen receptor α andor progesterone receptors and H.docx
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Coexpression of steroid hormone receptors estrogen receptor α andor progesterone receptors and H.docx
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CoexpressionofsteroidhormonereceptorsestrogenreceptorαandorprogesteronereceptorsandH
Co-expressionofsteroidhormonereceptors(estrogenreceptorαand/orprogesteronereceptors)andHer2/neu(c-erbB
-2)inbreastcancer:
Clinicaloutcomefollowingtamoxifen-basedadjuvanttherapy
FranciscoE.Gagoa,MarielA.FanellibandDanielR.Cioccab,
aGynecologyDepartment,MedicalSchool,NationalUniversityofCuyo,ParqueGral,SanMartín,5500Mendoza,Argentina
bLaboratoryofOncology,InstituteofExperimentalMedicineandBiologyofCuyo,NationalResearchCouncil(IMBECU-CONICET)andArgentineFoundationforCancerResearch,CasilladeCorreo,855-5000Mendoza,Argentina
TheJournalofSteroidBiochemistryandMolecularBiology
Volume98,Issue1,January2006,Pages36-40
Abstract
Inbreastcancerpatients,theexpressionofsteroidhormonereceptors(HR:
ERα/PR)appearsinverselycorrelatedwithHer2/neu(notallreportsagreeonthisnegativecorrelation).Moreover,somebutnotallstudiessuggestthatHR+/Her2/neu+patientshaveapoorresponsetoendocrinetherapy,makingthisspecialgroupamatterofdebate.InthisprospectivestudywehaveanalyzedtheclinicaloutcomeofourHR+/Her2/neu+patients(n = 51)selectedfrom516consecutivestagesI–IIcases,withafollow-up5–10years(mean7.3),treatedwithstandardadjuvanttherapywithtamoxifen(TAM)(TAMaloneorTAMafterchemotherapy).ThisgroupwascomparedwiththeHR+/Her-2/neu−patients(n = 129)treatedalsowithTAM.Thetumorbiopsieswerestudiedbyimmunohistochemistry.WefoundthattheassociationHR+/Her2/neu−was2.5timeshigherthantheassociationHR+/Her2/neu+(25%versus9.9%,respectively).Ourstudyalsoshowedthatthediseasefreesurvival(DFS)ofthepatientsco-expressingHRandHer2/neuwassignificantlylowerthanthoseexpressingHRbutlackingofHer2/neu(p < 0.001).Asimilarresultwasobtainedwhentheoverallsurvival(OS)wasevaluated(p = 0.001).AllofthesepatientsreceivedhormonetherapywithTAM,aloneorafterchemotherapy.WhentheanalysiswasperformedinthepatientstreatedwithTAMalone,againtheexpressionofHer-2/neuhadanegativeimpactonboththeDFSandtheOS(p < 0.05).
Keywords:
Estrogenreceptors;Progesteronereceptors;Her-2/neu;
Breastcancer
;Tamoxifen
ArticleOutline
1.Introduction
2.Patientsandmethods
2.1.Patientsandtreatments
2.2.Microscopicexaminations
2.3.Statisticalanalyses
3.Results
4.Discussion
Acknowledgements
References
1.Introduction
Twoimportantpredictivemolecularfactorsarecurrentlyinuseinbreastcancerpatients:
(a)hormonereceptors(HR)(estrogenreceptorα,ERα;progesteronereceptors,PR)whichpredicttheresponsetoendocrinetherapy,and(b)Her2/neu(alsoknownasc-erbB-2,humanepidermalgrowthfactorreceptor-2)whichpredictstheresponsetoHer2/neutargetedagents(e.g.,trastuzumab:
Herceptin™).InhumanbreastcancersithasbeenreportedthattheexpressionofHRcorrelatesnegativelywithHer-2/neuamplification/expression[1],[2]and[3],butnotallreportsagreeonthisnegativecorrelation[4].ThereiscontroversyalsoontheefficacyofhormonetherapyinbreastcancerpatientswhosetumorcellscontainbothHRandHer2/neu,severalstudieshavereportedapoorresponsetohormonetreatmentinHR+/Her2/neu+patients[5],[6],[7],[8]and[9].Thebasesforthisisthattamoxifen(TAM),atleastinpart,exertsitstherapeuticeffectthroughgrowthfactornetworksthatarehighlyinteractivewithERsignalinginthecontrolofbreastcancergrowthcausingapartialinhibitionorimpededantiproliferativeresponsetoendocrinetherapy[10].Molecularcross-talkbetweenERandHer2/neupathwayswasfoundincreasedinMCF-7cellsengineeredtooverexpressHer2/neuandinthesecellsTAMstimulatedcellgrowth[11].Anotherreasonistherelativelyreduced(butnotlackof)HRexpressioninHer2/neu+tumors(inthesecasestheefficacyofthetreatmentisdiminishedcomparedwithtumorswithhighHRcontent)[12].Finally,ithasbeenpointedoutthattheeffectofestradiolonERαexpressionandactivityismediatedbyHer2/neu,thatthereisbindingofestradioltomembraneERαandinteractionwithaheterodimercontainingHer2/neuleadingtotyrosinephosphorylationandactivationofAkt,aserine/threoninekinaseanddownstreamtargetofPI3-K(TAMonlypartiallyinhibitscellgrowthintheseconditions)[13].
Incontrast,anotherresearchershavenotfoundanegativeimpactofHer2/neuontheresponsetoendocrinetherapyinHR+patients[14],[15]and[16].Forexample,Loveetal.[16]concludethatHer2/neuoverexpressiondoesnotadverselyandmayfavorablyinfluenceresponsetoadjuvanthormonetherapy(oophorectomyandTAM)inHR+patients.Thediscrepancybetweenthepreclinicalandclinicaldatahasbeendiscussedinarecentarticle[17].
Inthepresentstudy,wehaveanalyzedtheclinicaloutcomeofourbreastcancerpatientswhosetumorsco-expressedHR(ERαand/orPRwereconsideredpositivewhenthenuclearreceptorsappearedin≥10%ofcancercells)[18]andHer2/neuandthatweretreatedwithhormonetherapy.Thesepatientswereselectedfromourtumorbank,themainclinicalcharacteristicsare:
consecutivebreastcancerpatientswithstageI–IIdisease,n = 516,follow-up5–10years,treatedaccordingtostandardprotocols.Inthesepatients,thetumorbiopsieshavebeenstudiedbyimmunohistochemistrytointegratethemolecularmarkersERα,PR,PCNA,Her2/neu,p53andP170withtheclinicopathologicaldatatoobtainprognosticinformation[18].WereportheretheDFSandOSofthegroupofHR+/Her2/neu+patients(n = 51)treatedwithendocrineadjuvanttherapy(TAMaloneorchemotherapyfollowedbyTAM),comparingtheclinicaloutcomeofthesepatientswiththosethatwereHR+/Her2/neu−(n = 129)andthatweretreatedwithTAM.
2.Patientsandmethods
2.1.Patientsandtreatments
Thisprospectivestudyinvolved516consecutivebreastcancerpatientsfromtheProvinceofMendoza(populationprincipallyformedbydescendantsofSpanishandItalianimmigrants)withuntreatedprimarybreastcancer(stageIandIIdisease),whoconsultedfrom1989to1998.Patientswerefirsttreatedwithsurgicaltherapy(mostreceivedconservativetumorresectionwithaxillarylymphnodedissection,afewpatientsoptedformastectomy).Informedconsentwasobtainedfrompatients.Standardadjuvantchemotherapy(CMF:
cyclophosphamide,methotrexate,fluorouracil;FAC/FEC:
fluorouracil,doxorubicin/epirubicin,cyclophosphamide)wasadministeredfollowedbyradiotherapy(40–50 Gytothechestwalland50 Gytothelymphnodes)whenindicated(accordingtothesurgicaltreatmentreceived,tumorsize,lymphnodeinvolvement,patient'sage,clinicalsituation).Followingthesetreatments,TAM(20 mg/dayfor5years)wasadministeredwhenindicated(takenintoaccounttheclinicopathologicalsituationandtheHRstatus).SomepatientsreceivedTAMaloneaftertheloco-regionaltreatment;thisdecisionwasbasedagainontheclinicopathologicalsituationandtheHRstatus.Thedifferenttreatmentmodalitieswereexplainedtothepatientsinadvanceandtheiropinionalsoinfluencedthetreatmentbutinaminorpercentageofthecases(e.g.,somerefusedadjuvantchemotherapyandoptedforTAMalone).Thepatientshavebeenfollowedonaregularoutpatientbasisthroughroutineclinicalandlaboratoryexaminations(includingX-ray,liverultrasound,andbonescanning);thesedatawerecomputerizedandregularlyupdated.Themeanfollow-upwas7.3years(S.D.2.1).Distantmetastasesanddeathweretheimportanteventsforthepresentstudysincetheyprovidedthediseasefreesurvival(DFS)andoverallsurvival(OS),respectively.Table1summarizesthemainclinicaldataoftheHR+/Her2/neu+andHR+/Her2/neu−patientsthatreceivedadjuvantendocrinetherapy.Theotherpatients(n = 336)didnotreceiveadjuvantendocrinetherapy,theyreceivedadjuvantstandardchemotherapyornoadjuvanttreatments.
Table1.
Mainclinicalcharacteristicsofthepatientsenteredintothestudy
Group
Agea(years)
Adjuvanttreatment
Number
I—HR+/Her2/neu+
51/516(9.9%)
1
68(55–82)
TAM
21/51(41.2%)
2
49(31–66)
Chem + TAM
30/51(58.8%)
II—HR+/Her2/neu−
129/516(25%)
3
65(39–86)
TAM
129
Full-sizetable
Abbreviationsused:
HR,steroidhormonereceptors(estrogenreceptoralphaand/orprogesteronereceptors);TAM,tamoxifen;Chem,chemotherapy(standardCMForFAC/FEC).
a Ageexpressedas:
mean(maximumandminimum).
ViewWithinArticle
2.2.Microscopicexaminations
Apathologistwaspresentatsurgeryperformingfrozensectionsforrapiddiagnosisandcontrollingthetumorsizeonfreshtissue.Alltumorsobtainedatsurgerywereimmediatelyfixedin10%bufferedformalinfor24–48 h,dehydrated,andembeddedinparaffin.Fordelayedhistopathologicalstudies,deparaffinizedtissuessection(5 μm-thick)werestainedwithhematoxylinandeosin.Forimmunohistochemistry(performedasreportedelsewhere[18]),serial5 μm-thicksectionsweremountedonto3-aminopropyltrietoxysilane(Sigma,St.Louis,MO)-coatedslidesforsubsequentanalysis.Thefollowingprimaryantibodieswereusedinimmunohistochemistry:
(1)mousemonoclonalantibody(MAb)1D5(DakoCorporation,Carpinteria,CA,USA)againstN-terminaldomain(A/Bregion)ofrecombinanthumanERα[19]usedat1:
100dilution.
(2)MouseMAbmPRIagainstPR(Transbio,SARL,France)[20]usedat1:
100dilution.(3)RabbitaffinitypurifiedpolyclonalantibodyagainstasyntheticpeptideoftheHer2/neuoncoprotein(21N)usedat1:
100dilution.TheimmunostainingobtainedwiththisantibodywasvalidatedbyWesternblot[2],andtheWesternblotwasvalidatedbySouthernblot[1].Anantig
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