Abstract 5255: Comparison of high-fructose and standard diets in methylnitrosourea (MNU)-induced ER+ mammary cancers: Altered carcinogenesis, differential effects of metformin, and metabolomic differences
Authors: Miller Mark S. , Grubbs Clinton J. , Stirdivant Steve , Lubet Ronald A. 
Published: July 2017

Abstract
The MNU-induced model of ER+ mammary cancers in Sprague-Dawley rats has routinely been employed in screening for chemopreventive agents. We recently reported that metformin was ineffective in preventing mammary cancers in rats on a standard diet (Thompson, et al, Cancer Prev. Res, 8, 231-9, 2015). In this study, we evaluated the carcinogenic response in Vehicle-treated rats and rats receiving Metformin (150 mg/Kg BW/day) on standard Teklad or isocaloric High-Fructose diets. In the first study, rats were placed on Teklad or High-Fructose diet at 43 days of age. At 100 days of age, animals were administered a single dose of MNU. Animals were administered Metformin or tamoxifen beginning 5 days later. Rats were palpated weekly for mammary tumors and sacrificed at 300 days of age. Body weights between groups were not different. Tumor multiplicity and tumor weights were: Vehicle-Teklad,1.15 and 1.44g; Vehicle- High-Fructose, 2.10 and 2.94g; Metformin-Teklad, 1.25 and 1.91g; Metformin -High-Fructose, 1.00 and1.99g. Tamoxifen resulted in the prevention of all tumors. High-Fructose alone resulted in a 2X increase in tumor multiplicity (P&lt;0.05) and tumor weights (P&lt;0.05). In the Teklad diet, Metformin marginally increased tumor multiplicity and weights (0.1&gt;P&lt;0.05). In the High-Fructose diet, Metformin decreased tumor multiplicity by 50% (P&gt;0.05). In the second study, which parallels the standard MNU model, rats were also placed on Teklad or High-Fructose diet at 43 days of age. At 50 days of age, rats were administered a single dose of MNU. Rats on High-Fructose diet were administered either Vehicle or Metformin, while rats on Teklad diet were given only Vehicle; beginning 5 days later. Rats were palpated weekly and sacrificed at 170 days of age. Body weights between groups were not different. Tumor multiplicity and tumor weights were: Vehicle-High-Fructose, 6.00 and 7.74g; Metformin High-Fructose, 5.00 and 6.17g; and Vehicle-Teklad, 2.70 and 5.75g. As indicated, Vehicle-treated rats on High-Fructose diet had twice the number of cancers as Vehicle-Teklad diet (P&lt;0.05). Metformin had a minimal effect in rats on a High-Fructose diet; unlike our previous results in rats ( receiving MNU at 50 days of age) on Teklad or High-Fat diet where metformin increased cancer multiplicity and cancer weights. Furthermore, we performed metabolomic studies on both serum and cancers from animals on Teklad and High-Fructose diets. It was observed (based on principal component analysis) that serum from rats on High-Fructose and standard Teklad diet were profoundly different. Furthermore, there appeared to be a metabolic signature in rats bearing cancers. These and other metabolomic changes will be presented. Supported by NCI contract number HHSN261201200021I, Task Order HHSN26100005.
Citation Format: Mark S. Miller, Clinton J. Grubbs, Steve Stirdivant, Ronald A. Lubet. Comparison of high-fructose and standard diets in methylnitrosourea (MNU)-induced ER+ mammary cancers: Altered carcinogenesis, differential effects of metformin, and metabolomic differences [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5255. doi:10.1158/1538-7445.AM2017-5255