OverexpressionandactivationofHER-2/neu(alsoknownasc-erbB-2),aproto-oncogene,wasfoundinabout30%ofhumanbreastcancers,promotingcancergrowthandmakingcancercellsresistanttochemo-andradio-therapy.Wild-typep53iscrucialinregulatingcellgrowthandapoptosisandisfoundtobemutatedordeletedin60-70%ofhumancancers.Andsomecancerswithawild-typep53donothavenormalp53function,suggestingthatitisimplicatedinacomplexprocessregulatedbymanyfactors.Inthepresentstudy,weshowedthattheoverexpressionofHER-2/neucoulddecreasetheamountofwild-typep53proteinviaactivatingPI3Kpathway,aswellasinducingMDM2nucleartranslocationinMCF7humanbreastcancercells.BlockageofPI3KpathwaywithitsspecificinhibitorLY294002causedG1-Sphasearrest,decreasedcellgrowthrateandincreasedchemo-andradio-therapeuticsensitivityinMCF7cellsexpressingwild-typep53.However,itdidnotincreasethesensitivitytoadriamycininMDA-MB-453breastcancercellscontainingmutantp53.OurstudyindicatesthatblockingPI3KpathwayactivationmediatedbyHER-2/neuoverexpressionmaybeusefulinthetreatmentofbreasttumorswithHER-2/neuoverexpressionandwild-typep53.
