miR-9 Regulation of BRCA1 and Ovarian Cancer Sensitivity to Cisplatin and PARP Inhibition

Abstract

BACKGROUND: Expression of BRCA1 is commonly decreased in sporadic ovarian cancer, and this is associated with platinum sensitivity and favorable prognosis. However, multiple mechanisms underlying low BRCA1 expression are not fully understood. METHODS: A bioinformatics-driven microRNA (miR) library screening was used to identify miRs that regulate BRCA1 expression. The effects of miR-9 on cisplatin (cDDP) and PARP inhibitor sensitivity were measured in ovarian cancer cells and C13* xenograft mice (n = 6 per group). The roles of miR-9 on prognosis were assessed in a cohort of ovarian cancer patients (n = 113) with Kaplan-Meier and Cox proportional hazards analyses. All statistical tests were two-sided. RESULTS: Reverse miR library screening revealed that miR-9 reduced the normalized luciferase activity to 60.3% (95% confidence interval [CI] = 52.0% to 68.5%; P < .001). miR-9 bound directly to the 3'-UTR of BRCA1 and downregulated BRCA1 expression in ovarian cancer cells. Treatment with miR-9 agomiR sensitized BRCA1-proficient C13* xenograft tumors to cisplatin and AG014699. In serous ovarian cancer, higher levels of miR-9 were inversely correlated with BRCA1 expression (Spearman rank correlation: R (2) = 0.379; P = .003). Patients with higher levels of miR-9 had better chemotherapy response, platinum sensitivity, and longer progression-free survival (PFS) (high vs low miR-9 expression: median PFS = 26.4 months, 95% CI = 13.8 to 39.0 months vs median PFS = 15.4 months, 95% CI = 6.8 to 23.9 months, P = .01). CONCLUSIONS: miR-9 mediates the downregulation of BRCA1 and impedes DNA damage repair in ovarian cancer. miR-9 may improve chemotherapeutic efficacy by increasing the sensitivity of cancer cells to DNA damage and may impact ovarian cancer therapy.