Up-regulation of miR-1245 by c-myc targets BRCA2 and impairs DNA repair

Abstract

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 BRCA2 3'-UTR and translation, impaired homologous recombination (HR)-mediated repair, reduced DNA damage-induced Rad51 nuclear foci, and rendered cells hypersensitive to γ-irradiation (IR), ultimately 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.