Document Type : Original Article
Authors
1
Department of Clinical Laboratory Sciences, School of Allied Medicine, Lorestan University of Medical Sciences. Khorramabad. Iran.
2
Hyperlipidemia Research Center, Department of Clinical Biochemistry, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
3
Department of Anatomical Science, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran.
4
Department of Laboratory Sciences, Lahijan Branch, Islamic Azad University, Lahijan, Iran.
5
Razi Herbal Medicines Research Center, Lorestan University of Medical Sciences. Khorramabad. Iran
6
Department of Biochemistry, School of Medicine, Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
7
Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.
8
Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
Abstract
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.
Keywords