Abstract 943: Obesity, P13k/Akt/mTOR signaling and prostate carcinogenesis in HiMyc mice

Abstract

Abstract Obesity has increased over the last 30 years in the U.S. and is associated with increased mortality rates for various cancers, including prostate cancer. In contrast, calorie restriction (CR) has been shown to act as a potent inhibitor of tumorigenesis. While this association between dietary energy balance and cancer has been clearly established, the mechanisms underlying these effects are poorly understood. To study the role of obesity and dietary fat in prostate cancer, we have used the HiMyc transgenic mouse model, a well-characterized model for the study of prostate carcinogenesis. For the current studies, HiMyc mice at weaning were placed on three dietary regimens [30% CR, 10kcal% fat (AIN76A), 60 kcal% fat], therefore generating lean, overweight and obese phenotypes. Groups of mice were then sacrificed at 3 and 6 months of age and urogenital tracts were removed and embedded in paraffin for histological analyses. In separate groups of mice, ventral prostate (VP) was removed and used to generate protein lysates for Western blot analyses. Histopathologic evaluation revealed a variety of lesions, with the severity of the lesion correlating with caloric intake. All diet groups had approximately similar incidence of hyperplasia and low grade PIN at 3 and 6 months of age. However, the different energy diets primarily affected the progression of premalignant lesions to malignant lesions in the ventral prostate. At 6 months, diet induced obesity (DIO; 60 kcal% fat) significantly increased the incidence of adenocarcinoma with aggressive stromal invasion, as compared to the overweight control group (96% vs. 65% respectively, p=0.0221), while only in situ carcinomas but no invasive adenocarcinomas were observed in mice maintained on the CR diet. Immunohistochemistry was performed on additional sections to evaluate differences in activation or total levels of Akt, mTOR, P-S6 ribosomal, angiogenesis markers and cell cycle markers. DIO increased, while CR reduced activation of signaling through both Akt and mTOR. Similar effects were observed for levels of cyclin D1 and CD31 proteins. Western blot analyses performed on protein lysates from VP of mice maintained on the same dietary regimen for 6 months confirmed these differential effects of dietary energy balance on Akt and mTOR signaling. The observed changes in signaling appeared to be due, at least in part, to changes in signaling through the insulin-like growth factor 1 receptor (IGF-1R) as a result of altered levels of circulating IGF-1. Taken together, these findings suggest that pathways activated by obesity, such as the Akt and mTOR pathways, may be key targets for preventing and controlling obesity-related prostate cancer progression. Supported by grant CA 107588 and MD Anderson Prostate Spore grant CA 140388. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 943.