Metformin accumulation correlates with organic cation transporter 2 protein expression and predicts mammary tumor regression in vivo

L. Allyson Checkley, Michael C. Rudolph, Elizabeth A. Wellberg, Erin D. Giles, Reema S. Wahdan-Alaswad, Julie A. Houck, Susan M. Edgerton, Ann D. Thor, Pepper Schedin, Steven M. Anderson, Paul S. MacLean

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)198-207
Number of pages10
JournalCancer Prevention Research
Volume10
Issue number3
DOIs
StatePublished - Mar 1 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Checkley, L. A., Rudolph, M. C., Wellberg, E. A., Giles, E. D., Wahdan-Alaswad, R. S., Houck, J. A., Edgerton, S. M., Thor, A. D., Schedin, P., Anderson, S. M., & MacLean, P. S. (2017). Metformin accumulation correlates with organic cation transporter 2 protein expression and predicts mammary tumor regression in vivo. Cancer Prevention Research, 10(3), 198-207. https://doi.org/10.1158/1940-6207.CAPR-16-0211-T