Mir-125a-3p Inhibits Er Alpha Transactivation And Overrides Tamoxifen Resistance By Targeting Cdk3 In Estrogen Receptor-Positive Breast Cancer

Tamoxifen (TAM) is a major adjuvant therapy for patients who are diagnosed with estrogen receptor-alpha (ER)-positive breast cancer; however, TAM resistance occurs often during treatment and the underlying mechanism is unclear. Here, we report that miR-125a-3p inhibits ER alpha transcriptional activity and, thus, ER+ breast cancer cell proliferation, which causes cell-cycle arrest at the G(1)/S stage, inducing apoptosis and suppressing tumor growth by targeting cyclin-dependent kinase 3 (CDK3) in vitro and in vivo. In addition, CDK3 and miR-125a-3p expression levels were measured in 37 cancerous tissues paired with noncancerous samples, and their expression levels were negatively associated with miR-125a-3p level. Of interest, miR-125a-3p level is down-regulated in MCF-7 TAM resistant (TamR) cells. Of more importance, up-regulation of miR-125a-3p resensitizes MCF-7 TamR cells to TAM, which is dependent on CDK3 expression. These results suggest that miR-125a-3p can function as a novel tumor suppressor in ER+ breast cancerby targeting CDK3, which may be a potential therapeutic approach for TamR breast cancer therapy.