Abstract 824: Altered growth factor and inflammatory signaling is associated with obesity related prostate cancer progression in HiMyc mice

Obesity is a long-term consequence of energy imbalance that occurs when energy intake exceeds expenditure 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. In addition, inflammation has been described to play an important role in carcinogenesis in many tissues. In this study, we have evaluated the effect of both CR and diet induced obesity (DIO) diets on prostate cancer progression in HiMyc mice. Four week old male HiMyc mice were placed on three dietary regimens [30% CR, 10kcal% fat (AIN76A), 60 kcal% fat], thus generating lean, overweight and obese phenotypes. Mice were then sacrificed at 3 and 6 months of age and urogenital tracts were removed and embedded in paraffin for histological analyses. Histopathologic evaluation of the prostate tissue revealed a variety of prostate 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 DIO 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, S6 ribosomal, Stat3, NFkB, angiogenesis markers, cell cycle markers and inflammatory cells. 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. In addition, levels of phospho-NFkB (p65) were increased in the DIO group, coupled with the presence of increased numbers of T-lymphocytes and macrophages. Western blot analyses were also performed on protein lysates from the VP of mice maintained on the same dietary regimens for 6 months and confirmed these differential effects of dietary energy balance on Akt/mTOR signaling and Stat3 activation. 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 enhanced growth factor (Akt/mTOR and Stat3) and inflammatory (NFkB) signaling may play a role in the diet-induced obesity effects on prostate cancer progression in HiMyc mice. These pathways may represent key targets for preventing and controlling obesity-related prostate cancer progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 824. doi:10.1158/1538-7445.AM2011-824