Abstract 824: Effects of metfornin on mammary carcinogenesis and metabolic profiles in methylnitrosourea-treated rats on standard or Western diets

Abstract

Abstract The methylnitrosourea-induced model of ER+ mammary cancer in female Sprague-Dawley rats has been routinely used to screen for chemopreventive agents. We recently reported that metformin was ineffective in reducing cancer formation in rats on a standard (4% fat) diet (Thompson, et al., Cancer Prev Res. 8, 231, 2015). In the present studies, rats were placed on a standard (Teklad) diet or on a Western diet (20% fat, low calcium) at 43 days of age (DOA), and administered MNU at 50 DOA. Rats were administered metformin or vehicle daily by gavage beginning at 57 days of age. Serum from the rats of the various groups was obtained both at 21 days following initial administration of metformin (or vehicle) and at the end of the study (when tumors had developed in most rats). We found an increase in the final body weights, number of mammary cancers, and the final weights of tumors in rats on western diet compared with standard diet. Furthermore, metformin failed to decrease tumor multiplicity in either diet, in fact, it increased final cancer weights (P<.05). Serum from rats in the various groups were examined for approximately 500 metabolites (Metabolon; Research Triangle Park, NC). The Metabolites which were differentially expressed when comparing Western vs standard diets at either time point included myoinositol, scyllo-inositol, 2-hydroxydecanoate, carnitine, tocopherol, and nicotinamide. Certain of these were fatty acids and lipid soluble vitamins that one would expect to be altered by diet. We also compared serum from animals on standard or Western diets at the early or late time points to determine metabolites associated with cancer development. Metabolites whose levels changed in tumor bearing rats included 4-OH-butyrate, acetyl-carnitine, uranate, and threonate. Finally, we compared the effects of metformin treatment in rats on Western or standard diet and found that the metabolic changes associated with metformin treatment were dependent on the diet employed. Thus, metformin altered levels of arachidate and serotonin only in rats on standard diet, while carnnitine and N-delta-acetylornithine were only modulated in rats on Western diet. Again, the most striking result may be that we still failed to observe any efficacy of metformin in animals on standard or Western diet. Citation Format: Mark S. Miller, Matthew D. Thompson, Ronald A. Lubet, Vernon E. Steele, Harold E. Seifried, Clinton J. Grubbs. Effects of metfornin on mammary carcinogenesis and metabolic profiles in methylnitrosourea-treated rats on standard or Western diets. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 824.