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Several epidemiologic studies have associated metformin treatment with a reduction in breast cancer incidence in prediabetic and type II diabetic populations. Uncertainty exists regarding which patient populations and/or tumor subtypes will benefit from metformin treatment, and most preclinical in vivo studies have given little attention to the cellular pharmacology of intratumoral metformin uptake. Epidemiologic reports consistently link western-style high fat diets (HFD), which drive overweight and obesity, with increased risk of breast cancer. We used a rat model of HFD-induced overweight and mammary carcinogenesis to define intratumoral factors that confer metformin sensitivity. Mammary tumors were initiated with 1-methyl-1-nitrosourea, and rats were randomized into metformin-treated (2 mg/mL drinking water) or control groups (water only) for 8 weeks. Two-thirds of existing mammary tumors responded to metformin treatment with decreased tumor volumes ( P &lt; 0.05), reduced proliferative index ( P &lt; 0.01), and activated AMPK ( P &lt; 0.05). Highly responsive tumors accumulated 3-fold greater metformin amounts ( P &lt; 0.05) that were positively correlated with organic cation transporter-2 (OCT2) protein expression ( r = 0.57; P = 0.038). Importantly, intratumoral metformin concentration negatively associated with tumor volume ( P = 0.03), and each 10 pmol increase in intratumoral metformin predicted &gt;0.11 cm 3 reduction in tumor volume. Metformin treatment also decreased proinflammatory arachidonic acid &gt;1.5-fold in responsive tumors ( P = 0.023). Collectively, these preclinical data provide evidence for a direct effect of metformin in vivo and suggest that OCT2 expression may predict metformin uptake and tumor response. Cancer Prev Res; 10(3); 198-207. ©2017 AACR .

Metformin Accumulation Correlates with Organic Cation Transporter 2 Protein Expression and Predicts Mammary Tumor Regression In Vivo