MiR-592 Attenuates Tamoxifen Resistance in Breast Cancer Through PIK3CA-Mediated PI3K/AKT/mTOR Signaling Pathway.

Abstract

Tamoxifen (TAM) is vital in breast cancer (BC) treatment, yet its resistance significantly impairs its efficacy. While miR-592 is known for its suppressive role in BC, its effect on chemotherapy resistance remains unclear. In this study, we observed a significant reduction in miR-592 levels in TAM-resistant BC tissues and cell lines. Low miR-592 expression was significantly associated with advanced TNM stage, lymph node metastasis, and poorer patient survival. Dual-luciferase assay confirmed miR-592 binding to the predicted gene PIK3CA. Increasing miR-592 levels decreased the IC50 of TAM, inhibited cell viability, migration, and invasion, and enhanced apoptosis in vitro, which was mimicked by PIK3CA knockdown and reversed by PIK3CA overexpression. Moreover, miR-592 upregulation suppressed tumor growth and improved TAM responsiveness in vivo. Molecularly, both si-PIK3CA and miR-592 mimics decreased the expression ratios of p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR, while increasing cleaved caspase-3 and E-cadherin expression in MCF-7/TAM cells. PIK3CA overexpression partially reversed these reductions. In conclusion, our study demonstrates that miR-592 attenuates TAM resistance by inhibiting the PIK3CA-driven PI3K/AKT/mTOR signaling pathway, representing a promising strategy to address chemoresistance in BC.