Rapamycin and mTOR a serendipitous discovery and implications for breast cancer 英文参考文献.docVIP

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Rapamycin and mTOR a serendipitous discovery and implications for breast cancer 英文参考文献.doc

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Rapamycin and mTOR a serendipitous discovery and implications for breast cancer 英文参考文献

SetoClinicalandTranslationalMedicine2012,1:29 /content/1/1/29 REVIEW OpenAccess RapamycinandmTOR:aserendipitousdiscovery andimplicationsforbreastcancer BelindaSeto Abstract RapamycinwasdiscoveredmorethanthirtyyearsagofromasoilsamplefromtheislandofRapaNui.Itwas isolatedfromStreptomyceshygroscopicusandinitialcharacterizationfocusedonitsantifungalactivities. Subsequentcharacterizationshowedthatithasimmunosuppressivepropertiesandhasbeenusedsuccessfullyto reduceorganrejectionwithkidneytransplantation.Rapamycinhasproventobeaversatilecompoundwithseveral seeminglyunrelatedproperties,includingantifungal,immunosuppressive,andanticancer.TheNationalCancer Institute(NCI)DevelopmentalTherapeuticsProgramdemonstratedthatrapamycininhibitedcellgrowthintumor celllines.Theseobservationsstimulatedresearchtoexploretheunderlyingmechanismofanti-tumoractivities.Cell growthinhibitioninvolvesbindingtothemammalianTargetofRapamycin(mTOR).ThemTORsignalingpathwayis criticaltocellgrowth,proliferation,andsurvivalandrapamycininhibitsthesehallmarkprocessesofcancer.Binding ofgrowthfactorsactivatesmTORsignaling,whichinturnleadstodownstreamphosphorylationofproteinkinases, e.g.,p70S6kinaseandlipidkinasesinthephosphorylationofphosphoinositides.UnderstandingofmTORsignaling providedthebiologicalbasisfortargetedchemotherapeuticsdevelopment,includingseveralrapamycinanalogues fortreatingbreastandothercancers. Keywords:Rapamycin,MammalianTargetofRapamycin(mTOR),Breastcancer,Targetedchemotherapeutics, Clinicaltranslation Review Introduction Thisreportdescribesataleofdiscoverythatreinforces the serendipitous nature of basic research and the no- Breast cancer is the second most commonly diagnosed tionthatdiscoveriesmayleadtounanticipatedoutcomes cancer, after skin cancer, among U.S. women. In 2012, inotherdisciplines.Inthisparticularstory,theisolation 227,000 new cases have been reported [1]. Recent ofthebacteriumStreptomyceshygroscopicusfromasoil developments in computed tomography imaging have sample thr