Dietary vitamin D exposure prevents obesity-induced increase in endometrial cancer in Pten^+/- mice

The possibility that dietary vitamin D₃ (VD₃) exposure inhibits endometrial carcinogenesis in an animal model and modifies the enhanced risk of endometrial carcinoma associated with obesity was investigated. At 4 weeks of age, Pten^+/- and wild-type mice were each divided into four treatment groups and fed AIN93G control diet, or AIN93G-based diet containing either 25,000 international units of VD₃ per kilogram of diet, 58% fat to induce obesity (high fat), or high fat and 25,000 international units of VD₃ per kilogram of diet. Mice were kept on these diets until they were sacrificed at week 28. Although VD₃ did not affect endometrial cancer risk, it inhibited obesity-induced increase in endometrial lesions. Specifically, high-fat diet increased focal glandular hyperplasia with atypia and malignant lesions from 58% in the control diet-fed Pten^+/- mice to 78% in obese mice. Dietary VD3 decreased the incidence of endometrial pathology in obese Pten^+/- mice to 25% (P < 0.001). VD3 altered the endometrial expression of 25-hydroxylase, 1α-hydroxylase, and vitamin D receptor in the wild-type and Pten ^+/- mice. Estrogen receptor-α mRNA levels were higher (P < 0.014) and progesterone receptor protein levels in the luminal epithelium were lower (P < 0.04) in the endometrium of control diet-fed Pten^+/- than wild-type mice, but the expression of these receptors was not affected by the dietary exposures. VD₃ reversed the obesity-induced increase in osteopontin (P < 0.001) and significantly increased E-cadherin expression (P < 0.019) in the endometrium of obese Pten^+/- mice. Our data confirm the known association between obesity and endometrial cancer risk. Dietary exposure to VD₃ inhibited the carcinogenic effect of obesity on the endometrium. This protective effect was linked to a reduction in the expression of osteopontin and increase in E-cadherin.