Grb7 Upregulation Is a Molecular Adaptation to HER2 Signaling Inhibition Due to Removal of Akt-Mediated Gene Repression 英文参考文献.docVIP

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Grb7 Upregulation Is a Molecular Adaptation to HER2 Signaling Inhibition Due to Removal of Akt-Mediated Gene Repression 英文参考文献.doc

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Grb7 Upregulation Is a Molecular Adaptation to HER2 Signaling Inhibition Due to Removal of Akt-Mediated Gene Repression 英文参考文献

Grb7UpregulationIsaMolecularAdaptationtoHER2 SignalingInhibitionDuetoRemovalofAkt-Mediated GeneRepression AlessioNencioni1*,MicheleCea1,AnnaGaruti1,MarioPassalacqua2,3,LizziaRaffaghello4 ,Debora Soncini1,EvaMoran1,GabrieleZoppoli1,VitoPistoia4,FrancoPatrone1,AlbertoBallestrero1 1DepartmentofInternalMedicine,CentreofExcellenceforBiomedicalResearch,UniversityofGenoa,Genoa,Italy,2DepartmentofExperimentalMedicine-Biochemistry Section,CentreofExcellenceforBiomedicalResearch,UniversityofGenoa,Genoa,Italy,3ItalianInstituteofBiostructuresandBiosystems(INBB),Rome,Italy,4Laboratory ofOncology,DepartmentofExperimentalandLaboratoryMedicine,G.GasliniInstitute,Genova,Italy Abstract Theefficacy ofanti-HER2therapeutics, suchaslapatinib andtrastuzumab,is limitedby primaryandacquiredresistance. Cellular adaptations that allow breast cancer cell to survive prolonged HER2 inhibition include de-repression of the transcriptionfactorFOXO3Awithconsequentestrogenreceptoractivation,and/orincreasedHER3signaling.Here,weused low-densityarrays,quantitativePCR,andwesternblottingtodeterminehowHER2signalinginhibitionwithlapatiniborPI3K inhibitors affects the expression of genes involved in breast cancer metastatic spread and overall prognosis. Retroviral + transgenesiswasusedtoexpressconstitutivelyactiveformsofAktintheHER2 breastcancercelllineSKBR3,andGrb7in MCF7cells.SpecificgenesilencingwasobtainedbysiRNAstransfection.AmurineBT474xenograftcancermodelwasused to assess the effect of lapatinib on gene expression in vivo. We found that lapatinib induces upregulation of Grb7, an adaptor protein involved in receptor tyrosine kinase signaling and promoting cell survival and cell migration. Grb7 upregulation induced by lapatinib was found to occur in cancer cells in vitro and in vivo. We demonstrate that Grb7 upregulationisrecreatedbyPI3KinhibitorswhilebeingpreventedbyconstitutivelyactiveAkt.Thus,Grb7isrepressedby PI3K signaling and lapatinib-mediated Akt inhibition is responsible for Grb7 de-