Metformin As a Potential Therapeutic Agent in Breast Cancer: Targeting MiR-125a Methylation and Epigenetic Regulation

Breast cancer, characterized by genetic diversity and molecular subtypes, presents significant treatment challenges, especially in human epidermal growth factor receptor type 2 (HER2)-positive cases, which are associated with poor prognosis. Metformin, widely known for its antidiabetic effects, has emerged as a promising candidate for cancer therapy. This study investigates the effect of metformin on miR-125a promoter methylation and its subsequent impact on the HER2 signaling pathway in HER2-positive breast cancer cells (SK-BR3). SK-BR3 cells were cultured and treated with various concentrations of metformin to assess its effects on cell viability, DNA methylation, HER2, and DNA Methyltransferase 1 (DNMT1) expression. Molecular analyses focus on the miR-125a signaling pathway modulation, DNA methylation, mRNA expression of DNMT1, and protein level of HER2. Research showed a dose-dependent reduction in cell viability, with IC50 values from 65 mM at 48 hours to 35 mM at 72 hours. Metformin treatment led to demethylation of the miR-125a promoter, which increased miR-125a expression and subsequently reduced HER2 levels. This suggests that metformin exerts its anticancer effects partly by regulation of the miR-125a-HER2 axis. Additionally, metformin inhibited vimentin expression, indicating its potential to interfere with epithelial-mesenchymal transition (EMT) processes. Metformin may serve as a targeted therapeutic agent in HER2-positive breast cancer by modulating the miR-125a-HER2 axis and influencing on the epigenetic and EMT regulation. Further research is warranted to elucidate the therapeutic potential of metformin through these mechanisms.