MiR-199a-3p was previously predicted to target tumor suppressor gene BRCA1, which has been linked to cancer onset and therapeutic response. In this study, the effects of miR-199a-3p-mediated BRCA1 dysfunction on triple-negative breast cancer (TNBC) progression and chemosensitivity were assessed. The association between miR-199a-3p and BRCA1 expression was examined in TNBC tumors and verified with luciferase reporter and protein assays. Tumorigenic functions of miR-199a-3p in TNBC cells were investigated by cell proliferation, clonogenic and migration assays. The sensitivities to chemotherapeutic drugs were tested with cisplatin and PARP inhibitor (veliparib) treatments. Mouse xenograft model was used to examine the effects of miR-199a-3p on tumor growth and drug response in vivo. MiR-199a-3p was shown to directly target BRCA1 in TNBC cells, resulting its downregulation and reduced luciferase reporter activity mediated by BRCA1 3'-UTR. Ectopic miR-199a-3p in TNBC cells exerted inhibitory effects on cell proliferation, migration and xenograft tumor growth. Moreover, miR-199a-3p was shown to reverse cisplatin-resistance and sensitize TNBC cells to veliparib, which might be due to repressed DNA repair ability and induced cell apoptosis. Our results demonstrated the tumor suppressive effects of miR-199a-3p on TNBC and induction on chemotherapeutic sensitivities, which were correlated with BRCA1 gene dysfunction. These findings may provide insights into the potential prognostic and therapeutic values of miR-199a-3p in patients with TNBC.
Keywords: BRCA1; MicroRNA; chemoresistance; triple negative breast cancer.
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