Small Molecule Antagonists of the WntBeta-Catenin Signaling Pathway Target Breast Tumor-Initiating Cells in a Her2Neu Mouse Model of Breast Cancer 英文参考文献.docVIP

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Small Molecule Antagonists of the WntBeta-Catenin Signaling Pathway Target Breast Tumor-Initiating Cells in a Her2Neu Mouse Model of Breast Cancer 英文参考文献.doc

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Small Molecule Antagonists of the WntBeta-Catenin Signaling Pathway Target Breast Tumor-Initiating Cells in a Her2Neu Mouse Model of Breast Cancer 英文参考文献

SmallMoleculeAntagonistsoftheWnt/Beta-Catenin SignalingPathwayTargetBreastTumor-InitiatingCellsin aHer2/NeuMouseModelofBreastCancer RobinM.Hallett,MariaK.Kondratyev,AndrewO.Giacomelli,AllisonM.L.Nixon,AdeleGirgis-Gabardo, DoraIlieva,JohnA.Hassell* DepartmentofBiochemistryandBiomedicalSciences,CentreforFunctionalGenomics,McMasterUniversity,Hamilton,Ontario,Canada Abstract Background:Recentevidencesuggeststhathumanbreastcancerissustainedbyaminorsubpopulationofbreasttumor- initiating cells (BTIC), which confer resistance to anticancer therapies and consequently must be eradicated to achieve durablebreastcancercure. Methods/Findings: To identify signaling pathways that might be targeted to eliminate BTIC, while sparing their normal stem and progenitor cell counterparts, we performed global gene expression profiling of BTIC- and mammary epithelial stem/progenitor cell- enriched cultures derived from mouse mammary tumors and mammary glands, respectively. Such analysessuggestedarolefortheWnt/Beta-cateninsignalingpathwayinmaintainingtheviabilityandorsustainingtheself- renewalofBTICsinvitro.TodeterminewhethertheWnt/Beta-cateninpathwayplayedaroleinBTICprocessesweemployed achemicalgenomicsapproach.WefoundthatpharmacologicalinhibitorsofWnt/b-cateninsignalinginhibitedsphere-and colony-formation by primary breast tumor cells and primary mammary epithelial cells, as well as by tumorsphere- and mammosphere-derived cells. Serial assays of self-renewal in vitro revealed that the Wnt/Beta-catenin signaling inhibitor PKF118–310irreversiblyaffectedBTIC,whereasitfunctionedreversiblytosuspendtheself-renewalofmammaryepithelial stem/progenitorcells.IncubationofprimarytumorcellsinvitrowithPKF118–310eliminatedtheircapacitytosubsequently seed tumor growth after transplant into syngeneic mice. Administration of PKF118–310 to tumor-bearing mice halted tumor growth in vivo. Moreover, viable tumor cells harvested from PKF118–310 treated mice were unable to seed the growthofsecondarytumorsaftertr