MicroRNA-375 promotes tamoxifen resistance by stabilizing ERα via UBE3A-mediated ubiquitination

Elucidating the molecular mechanisms of tumorigenesis and therapeutic resistance is essential for the development of effective treatments. Disruption of estrogen receptor alpha (ERα) signaling in ER⁺ breast cancer is a key driver of endocrine resistance, necessitating a deeper understanding of its regulatory mechanisms. MicroRNA-375 (miR-375) has been identified as a context-dependent regulator, functioning either as an oncogene or tumor suppressor in different cancer types. This study aimed to explore the role of miR-375 in breast cancer progression and tamoxifen resistance.

Quantitative reverse transcription PCR (qRT-qPCR) was used to assess miR-375 expression in breast cancer tissues and cell lines. The correlation between miR-375 expression and overall survival in breast cancer patients was analyzed using the Kaplan-Meier plotter. Functional roles of miR-375 in breast cancer and tamoxifen sensitivity were evaluated via in vitro and in vivo gain- and loss-of-function assays. The molecular mechanism involving the miR-375-UBE3A-ERα signaling axis was investigated using dual-luciferase reporter assays, immunoprecipitation (IP), immunofluorescence (IF), and Ubiquitination analyses.

miR-375 expression was significantly higher in ER⁺ breast cancer tissues compared to ER^- samples. Patients with high miR-375 levels exhibited significantly worse overall survival. Overexpression of miR-375 enhanced ERα protein stability; consequently, this led to the acquisition of malignant phenotypes, including enhanced proliferation, migration, invasion, and tamoxifen resistance, along with reduced apoptosis. These phenotypic effects were reversed upon miR-375 knockdown. Mechanistically, UBE3A, a direct target of miR-375, facilitated ERα degradation through the ubiquitin-proteasome pathway.

This study reveals that the miR-375-UBE3A-ERα axis contributes to breast cancer progression and tamoxifen resistance. Targeting miR-375 may represent a promising strategy to overcome endocrine resistance in ER⁺ breast cancer.