Antiandrogen Flutamide-Induced Restoration of miR-449 Expression Mitigates Molecular Markers Associated with Ovarian Cancer Risk

The involvement of the androgen receptor (AR) pathway in the development of epithelial ovarian cancer is increasingly recognized. We examined the effects of the anti-androgen agent flutamide on miRNA expression in women at high risk (HR) for ovarian cancer. Flutamide treatment restored the reduced expression of miR-449a and miR-449b-5p in HR tissues, thereby decreasing CSF1R and AR expression associated with an increased risk of ovarian cancer. In addition to the known direct binding of flutamide to the AR, we found that flutamide also suppresses AR expression via miR-449a and miR-449b-5p upregulation, revealing a novel dual-inhibitory mechanism on the AR pathway. Taken together, our study highlights the chemopreventive potential of flutamide in ovarian cancer and suggests avenues for future research and clinical applications. We conducted miRNA-sequencing profiling in the two ovarian cancer-related tissues, the ovary and fallopian tube, from HR and LR patients (with high- and low-risk for ovarian cancer, respectively). HR group was further divided into two cohorts: those treated with flutamide (the “flutamide” cohort) and those not treated with flutamide (the “HR” cohort). The samples across the three cohorts (flutamide, HR, and LR) were matched for body mass index (BMI) and menopausal status. The HR and flutamide cohorts were defined for the high-risk status and balanced for germline BRCA1/2 conditions