Metformin accumulation correlates with organic cation transporter 2 protein expression and predicts mammary tumor regression in vivo
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© 2017 AACR. 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 < 0.05), reduced proliferative index (P < 0.01), and activated AMPK (P < 0.05). Highly responsive tumors accumulated 3-fold greater metformin amounts (P < 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 > 0.11 cm3 reduction in tumor volume. Metformin treatment also decreased proinflammatory arachidonic acid > 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.
author list (cited authors)
Checkley, L. A., Rudolph, M. C., Wellberg, E. A., Giles, E. D., Wahdan-Alaswad, R. S., Houck, J. A., ... MacLean, P. S.
Mammary Neoplasms, Experimental
Organic Cation Transport Proteins
Organic Cation Transporter 2