Metformin Efficacy Against Breast Cancer Depends on Its Cellular Uptake via Cation Transporters and Modulation of Insulin/IGF1 Pathway

Clinical evidence suggests that metformin is efficacious as an anticancer agent in diabetic patients; however, results about its efficacy are mixed, especially in non-diabetic patients. The goal of this dissertation project was to improve metformin treatment for breast cancer by elucidating molecular and cellular mechanisms that play an important role in its efficacy. Research conducted in this project showed that breast cancer cells exhibit wide variability in the expression of cation transporters, which are required for intracellular uptake and accumulation of metformin. Further, metformin requires a functional intracellular adenosine monophosphate-activated protein kinase (AMPK) pathway to exert its anticancer activity. Interestingly, cancer stem cells, which are more sensitive to the antiproliferative effect of metformin, express higher levels of cation-selective transporters than non-stem cancer cells. Preclinical dose-response studies showed that estrogen receptor positive breast tumors with low expression of cation transporters required a minimum metformin dose (in combination with 30 mg/kg/day paclitaxel) that is equivalent to the highest current anti-diabetic dose of 2,550 mg/day, suggesting that an even higher metformin dose is needed to optimally treat these patients. The minimum efficacious metformin dose (in combination with 50 mg/kg/day carboplatin) to treat triple negative breast cancer with high expression of cation transporters was equivalent to the 850 mg daily dose of metformin that is typically used in the treatment of type 2 diabetes. Studies in mice showed that attenuation of the insulin/IGF1 pathway sensitized breast cancer cells to the antiproliferative efficacy of metformin exerted via modulation of the AMPK pathway. These results provide a rationale for lower efficacy of metformin in non-diabetic patients, and suggest that co-administration of metformin with an insulin/IGF1 pathway inhibitor may improve metformin efficacy in non-diabetic breast cancer patients. In summary, the dissertation research provides valuable insights into cellular and molecular factors that contribute to the variable responses of diabetic and non-diabetic breast cancer patients to metformin therapy. The findings of this research will contribute to improvement in selection of breast cancer patients who would respond to metformin therapy, improved dose selection strategy, and development of new metformin combination therapies for breast cancer.Doctor of Philosoph