BRCA2,a clinical prognostic factor,is significantly up-regulated in mRNA level,while its protein expression is often decreased in sporadic breast cancer.However,how BRCA2 protein expressions are suppressed in these tu...BRCA2,a clinical prognostic factor,is significantly up-regulated in mRNA level,while its protein expression is often decreased in sporadic breast cancer.However,how BRCA2 protein expressions are suppressed in these tumors remains unknown.In this study,we demonstrated that miR-1245 directly suppressed BRCA23′-UTR and translation,impaired homologous recombination(HR)-mediated repair,reduced DNA damage-induced Rad51 nuclear foci,and rendered cells hypersensitive to g-irradiation(IR),ul-timately inducing high chromosomal abnormalities in normal breast cells and breast cancer cells.Conversely,inhibiting miR-1245 in breast cancer cells enhanced BRCA2 levels and induced resistance to IR.Furthermore,we demonstrated that c-myc up-regulated miR-1245 expression via direct binding to the miR-1245 promoter,which led to down-regulation of BRCA2 and reduction in HR efficiency.Significantly,miR-1245 levels in primary breast tumors correlated with c-myc overexpression and BRCA2 suppression.These findings uncover a BRCA2 regulatory and signaling pathway in sporadic breast cancer and support a functionally and clinically relevant epigenetic mechanism in cancer pathogenesis.展开更多
基金supported by the National Natural Science Foundation of China (Nos.81071647,81071762,30872930,81071780,81030048,30870963,and 30831160517)the Science and Technology Department of Guangdong Province,China (No.S2011020002757)the Fundamental Research Funds for the Central Universities (No.10ykzd03).
文摘BRCA2,a clinical prognostic factor,is significantly up-regulated in mRNA level,while its protein expression is often decreased in sporadic breast cancer.However,how BRCA2 protein expressions are suppressed in these tumors remains unknown.In this study,we demonstrated that miR-1245 directly suppressed BRCA23′-UTR and translation,impaired homologous recombination(HR)-mediated repair,reduced DNA damage-induced Rad51 nuclear foci,and rendered cells hypersensitive to g-irradiation(IR),ul-timately inducing high chromosomal abnormalities in normal breast cells and breast cancer cells.Conversely,inhibiting miR-1245 in breast cancer cells enhanced BRCA2 levels and induced resistance to IR.Furthermore,we demonstrated that c-myc up-regulated miR-1245 expression via direct binding to the miR-1245 promoter,which led to down-regulation of BRCA2 and reduction in HR efficiency.Significantly,miR-1245 levels in primary breast tumors correlated with c-myc overexpression and BRCA2 suppression.These findings uncover a BRCA2 regulatory and signaling pathway in sporadic breast cancer and support a functionally and clinically relevant epigenetic mechanism in cancer pathogenesis.
