Metformin Accumulation Correlates with Organic Cation Transporter 2 Protein Expression and Predicts Mammary Tumor RegressionIn Vivo.
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 preclinicalin vivostudies 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 cm3reduction 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 metforminin vivoand suggest that OCT2 expression may predict metformin uptake and tumor response.Cancer Prev Res; 10(3); 198-207. ©2017 AACR.
Division of Endocrinology, Metabolism and Diabetes, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado.
L Allyson
LA
Checkley
Division of Endocrinology, Metabolism and Diabetes, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado.
Michael C
MC
Rudolph
Department of Pathology, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado.
Elizabeth A
EA
Wellberg
Department of Nutrition and Food Science, Texas A&M University, College Station, Texas.
Erin D
ED
Giles
Department of Pathology, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado.
Reema S
RS
Wahdan-Alaswad
Division of Endocrinology, Metabolism and Diabetes, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado.
Julie A
JA
Houck
Department of Pathology, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado.
Susan M
SM
Edgerton
Department of Pathology, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado.
Ann D
AD
Thor
Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, Oregon.|Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.
Pepper
P
Schedin
Department of Pathology, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado.
Steven M
SM
Anderson
Division of Endocrinology, Metabolism and Diabetes, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado. paul.maclean@ucdenver.edu.|Department of Pathology, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado.|Center for Human Nutrition, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado.
Paul S
PS
MacLean
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D008687:Metformin / Q000494:pharmacology*; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D000075102:Organic Cation Transporter 2; D051381:Rats; D017208:Rats, Wistar
D000970:Antineoplastic Agents; D007004:Hypoglycemic Agents; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C100590:Slc22a2 protein, rat; D008687:Metformin