Abstract 2888: Vitamin D inhibits obesity-induced endometrial carcinogenesis in Pten+/− mice

Abstract

Abstract Objectives: A growing body of epidemiologic and experimental evidence suggests that vitamin D may lower the risk of a number of epithelial malignancies. In this study, we sought to determine whether vitamin D exposure reverses endometrial carcinogenesis in an animal model, and further whether it modifies the enhanced risk of endometrial carcinoma associated with obesity. Methods: When 4 weeks of age, Pten+/− and wildtype (WT) mice were each divided into four treatment groups and fed an AIN93G based diet containing either (1) 18% energy from fat (control diet), (2) 18% fat and 25K IU of VD3/kg diet (VD3 supplemented control diet), (3) 58% fat to induce obesity (obesity inducing diet, OID), and (4) 58% fat and 25K IU of VD3/kg diet (VD3 supplemented OID). Mice were kept on these diets until they were sacrificed at 28 weeks of age. Results: Dietary VD3 exposure did it cause any apparent toxicity. VD3 increased the expression of 25-hydroxylase (25-OHase, an enzyme converting VD3 to 25(OH)D3) in the endometrium of WT (p<0.027) and Pten+/− mice (p<0.025). Further, it increased vitamin D receptor (VDR) levels (p<0.006) in the obese Pten+/− mice. Although VD3 did not affect endometrial cancer risk, it inhibited obesity-induced increase in endometrial cancer. Specifically, OID increased focal glandular hyperplasia with atypia and malignant lesions from 58% in the control diet fed Pten+/− mice to 78%. Dietary VD3 supplementation decreased the incidence of endometrial pathology in Pten+/− mice fed OID to 25% (p<0.001). Estrogen receptor (ER)-α mRNA levels were significantly higher (p<0.014) and progesterone receptor (PR) protein levels in the luminal epithelium were significantly lower (p<0.04) in the endometrium of control diet fed Pten+/− mice than in the WT mice, but the expression of ER-α, ER-β or PR mRNA, or epithelial or stromal protein expression were not affected by the dietary exposures. Conclusions: Our data obtained in Pten+/− mice confirm the known association between increased body weight and endometrial cancer risk. Dietary exposure to VD3 inhibited the carcinogenic effect of obesity on the endometrium; the mechanism mediating this protective effect was not linked to changes in the expression of ER-α, ER-β or PR. 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 2888.