Autophagy Facilitates the Development of Breast Cancer Resistance to the Anti-HER2 Monoclonal Antibody Trastuzumab 英文参考文献.docVIP

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Autophagy Facilitates the Development of Breast Cancer Resistance to the Anti-HER2 Monoclonal Antibody Trastuzumab 英文参考文献.doc

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Autophagy Facilitates the Development of Breast Cancer Resistance to the Anti-HER2 Monoclonal Antibody Trastuzumab 英文参考文献

AutophagyFacilitatestheDevelopmentofBreastCancer ResistancetotheAnti-HER2MonoclonalAntibody Trastuzumab AlejandroVazquez-Martin1,2,CristinaOliveras-Ferraros1,2,JavierA.Menendez1,2 * 1Catalan Institute of Oncology (ICO), Girona, Catalonia, Spain, 2Girona Biomedical Research Institute (IdIBGi), Dr. Josep Trueta University Hospital of Girona, Girona, Catalonia,Spain Abstract Autophagyhasbeenemerging asanovel cytoprotective mechanismtoincrease tumorcellsurvival underconditions of metabolicstressandhypoxiaaswellastoescapechemotherapy-inducedcelldeath.Toelucidatewhetherautophagymight alsoprotectcancercellsfromthegrowthinhibitoryeffectsoftargetedtherapies,weevaluatedtheautophagicstatusof preclinical breast cancer models exhibiting auto-acquired resistance to the anti-HER2 monoclonal antibody trastuzumab (Tzb).WefirstexaminedthebasalautophagiclevelsinTzb-naiveSKBR3cellsandintwopoolsofTzb-conditionedSKBR3 cells (TzbR), which optimally grow in the presence of Tzb doses as high as 200mg/ml Tzb. Fluorescence microscopic analyses revealed that the number of punctate LC3 structures -a hallmark of autophagy- was drastically higher in Tzb- refractorycellsthaninTzb-sensitiveSKBR3parentalcells.Immunoblottinganalysesconfirmedthatthelipidationproductof theautophagicconversionofLC3wasaccumulatedtohighlevelsinTzbRcells.HighlevelsoftheLC3lipidatedforminTzb- refractorycellswereaccompaniedbydecreasedp62/sequestosome-1proteinexpression,aphenomenoncharacterizingthe occurrenceofincreasedautophagicflux.Moreover,increasedautophagywasactivelyusedtosurviveTzbtherapyasTzbR pools were exquisitely sensitive to chemical inhibitors of autophagosomal formation/function. Knockdown of LC3 expression via siRNA similarly resulted in reduced TzbR cell proliferation and supra-additively interacted with Tzb to re- sensitizeTzbRcells.Sub-groupsofTzb-naiveSKBR3parentalcellsaccumulatedLC3punctatestructuresanddecreasedp62 expressionaftertreatmentwithhigh-doseTzb,likelypromotingtheirownresistance.Thisisthefirs