en Cancer Cancer Original Article Original Article <p><span style="font-size:11pt"><span style="line-height:107%"><span style="font-family:Calibri,sans-serif">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.</span></span></span><br> &nbsp;</p> Metformin, Breast cancer, miR-125a, methylation, HER2, DNMT1, epigenetics 272 285 http://ijmcmed.org/browse.php?a_code=A-10-262-5&slc_lang=en&sid=1 Fatemeh Ahmadpour ahmadpourfatimaa@gmail.com 100319475328460032725 100319475328460032725 No Department of Clinical Laboratory Sciences, School of Allied Medicine, Lorestan University of Medical Sciences. Khorramabad. Iran. Somayeh Igder igder_s@ajums.ac.ir 100319475328460032726 100319475328460032726 No Hyperlipidemia Research Center, Department of Clinical Biochemistry, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. Alireza Eftekhari Moghadam ali_eftekhari62@yahoo.com 100319475328460032727 100319475328460032727 No Department of Anatomical Science, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran. Bahman Moradipoodeh bmoradipoodeh@yahoo.com 100319475328460032728 100319475328460032728 No Department of Laboratory Sciences, Lahijan Branch, Islamic Azad University, Lahijan, Iran. Asma Sepahdar asma.sepahdar@gmail.com 100319475328460032729 0009-0001-8235-3066 No Razi Herbal Medicines Research Center, Lorestan University of Medical Sciences. Khorramabad. Iran. Poneh Mokarram Mokaram2@gmail.com 100319475328460032730 100319475328460032730 No Department of Biochemistry, School of Medicine, Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran Jafar Fallahi Jafarf80@gmail.com 100319475328460032731 100319475328460032731 No Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran Ghorban Mohammadzadeh mohammadzadeh@ajums.ac.ir 100319475328460032732 100319475328460032732 Yes Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.