Abstract 2809: Chemopreventive studies of multiple agents in the methylnitrosourea-induced ER+ mammary cancer model in animals on standard and Western diets

Abstract

Abstract Multiple positive and negative preventive agents [tamoxifen, vorozole (aromatase inhibitor), targretin (RXR agonist), gefitinib (EGFR inhibitor), metformin, and Lipitor] were examined for efficacy in rats given either standard Teklad (4% fat) diet or a modified Western diet [high fat (42%)]. Female Sprague Dawley rats were placed on the high fat or standard diet at 43 days of age, and administered methylnitrosourea (MNU) at 50 days of age. Rats on high fat diet vs standard diet gained approximately 40% more weight, exhibited a 50% increase in cancer multiplicity, and a decrease in cancer latency. The strong preventive agents (tamoxifen, vorozole, targretin, and gefitinib) were highly effective in animals on standard or high fat diets (reducing cancer multiplicity >75% in rats on either diet). It was unclear whether the altered physiology of animals on high fat diet or altered PK of agents in animals with higher fat content might alter activity of these agents. We had previously found that both metformin and Lipitor were ineffective in rats on a standard fat diet, but thought that they might be effective in rats on a high fat diet. Interestingly, neither compound decreased tumorigenesis; but, at least marginally, increased tumor incidence and final tumor weights in rats on both diets. The ability of the various agents to alter proliferation of normal mammary epithelium in MNU-treated rats exposed for 2 weeks to the various agents was determined. It was found that inhibition of proliferation in mammary epithelium corresponded well to the efficacy of these agents in long-term chemopreventive assays. These results demonstrated that: (1) a high fat diet can be employed in this rat model to increase tumor multiplicity; (2) tamoxifen, vorozole, targretin and gefitinib were highly effective in rats on standard or high fat diet; (3) metformin and Lipitor were ineffective with either diet; and (4) there is a correlation between inhibition of proliferation in normal mammary epithelium and long-term preventive efficacy of agents; but this may reflect the homogeneity of the rat mammary cancers. Supported by NCI contract HHSN261201200021I. Citation Format: Clinton J. Grubbs, Mark S. Miller, Vernon E. Steele, Fariba Moeinpour, Harold Seifried, Brandy M. Heckman-Stoddard, Ronald A. Lubet. Chemopreventive studies of multiple agents in the methylnitrosourea-induced ER+ mammary cancer model in animals on standard and Western diets. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2809. doi:10.1158/1538-7445.AM2015-2809