Abstract
Over the last several decades, a growing body of research has investigated the potential to repurpose the anti-diabetic drug metformin for breast cancer prevention and/or treatment. Observational studies in the early 2000s demonstrated that patients with diabetes taking metformin had decreased cancer risk, providing the first evidence supporting the potential role of metformin as an anti-cancer agent. Despite substantial efforts, two decades later, the exact mechanisms and clinical efficacy of metformin for breast cancer remain ambiguous. Here, we have summarized key findings from studies examining the effect of metformin on breast cancer across the translational spectrum including in vitro, in vivo, and human studies. Importantly, we discuss critical factors that may help explain the significant heterogeneity in study outcomes, highlighting how metformin dose, underlying metabolic health, menopausal status, tumor subtype, membrane transporter expression, diet, and other factors may play a role in modulating metformin's anti-cancer effects. We hope that these insights will help with interpreting data from completed studies, improve the design of future studies, and aid in the identification of patient subsets with breast cancer or at high risk for the disease who are most likely to benefit from metformin treatment.