Markers of Tumor-Initiating Cells Predict Chemoresistance in Breast Cancer 英文参考文献.docVIP

MarkersofTumor-InitiatingCellsPredict ChemoresistanceinBreastCancer ChangGong1.,HeruiYao1.,QiangLiu1,2,JingqiChen1,JunweiShi1,FengxiSu1,ErweiSong1,3* 1BreastTumorCenter,SunYat-SenMemorialHospital,SunYat-SenUniversity,Guangzhou,People’sRepublicofChina,2DepartmentofMedicalOncology,Dana-Farber CancerInstitute,Boston,Massachusetts,UnitedStatesofAmerica,3SchoolofLifeSciences,SunYat-SenUniversity,Guangzhou,People’sRepublicofChina Abstract Purpose: Evidence is lacking whether the number of breast tumor-initiating cells (BT-ICs) directly correlates with the sensitivity of breast tumors to chemotherapy. Here, we evaluated the association between proportion of BT-ICs and chemoresistanceofthetumors. Methods:Immunohistochemicalstaining(IHC)wasusedtoexaminetheexpressionofaldehydedehydrogenase1(ALDH1) and proliferating cell nuclear antigen, and TUNEL was used to detect the apoptosis index. The significance of various variablesinpatientsurvivalwasanalyzedusingaCoxproportionalhazardsmodel.ThepercentageofBT-ICsinbreastcancer + cell lines and primary breast tumors was determined by ALDH1 enzymatic assay, CD44 /CD242 phenotype and mammosphereformationassay. Results: ALDH1 expression determined by IHC in primary breast cancers was associated with poor clinical response to neoadjuvantchemotherapyandreducedsurvivalinbreastcancerpatients.Breasttumorsthatcontainedhigherproportion + of BT-ICs with CD44 /CD242 phenotype, ALDH1 enzymatic activity and sphere forming capacity were more resistant to neoadjuvantchemotherapy.ChemoresistantcelllinesAdrR/MCF-7andSK-3rd,hadincreasednumberofcellswithsphere + + formingcapacity,CD44 /CD242 phenotypeandside-population.RegardlesstheproportionofT-ICs,FACS-sortedCD44 / CD242cellsthatderivedfromprimarytumorsorbreastcancerlineswereabout10–60foldmoreresistanttochemotherapy + relativetothenon-CD44 /CD242cellsandtheirparentalcells.Furthermore,ourdatademonstratedthatMDR1(multidrug resistance1)andABCG2(ATP-bindingcassettesub-familyGmember2)wereupregulatedi