MP90-02 CARBOHYDRATE RESTRICTION OPPOSES TUMOR-PROMOTING EFFECTS OF OBESITY IN THE HI-MYC TRANSGENIC MOUSE MODEL OF PROSTATE CANCER.

Abstract

synthesis, in prostate cancer progression. We determined the impact of modifying serum cholesterol levels on tumor progression in PTENdeficient transgenic mouse model of prostate cancer. METHODS: PTEN-Cre mice consuming ad libitum high fat, high cholesterol diets (40% fat, 1.25% cholesterol) were randomized after weaning to receive the cholesterol uptake inhibitor, ezetimibe (Zetia; 30 mg/kg diet), or no intervention, and sacrificed at 2, 3, or 4 months of age. At sacrifice, prostates were removed, weighed, and fixed in formalin. Serum cholesterol and testosterone levels were measured by ELISA and prostate androgens measured by mass spectrometry. Proliferation and apoptosis in tumor epithelium and stroma was assessed by Ki67 and TUNEL assay, respectively. RESULTS: Mice randomized to Zetia had lower serum cholesterol levels (p1⁄40.031). Cholesterol levels were positively correlated with prostate weight (p1⁄40.033) and tumor epithelial proliferation (p1⁄40.069), and negatively correlated with tumor epithelial apoptosis (p1⁄40.004). Tumor stromal cell proliferation was reduced in the Zetia group (p1⁄40.010). Increased cholesterol levels were associated with elevated intraprostatic DHEA, testosterone and androstendione (p1⁄40.043, p1⁄40.074, p1⁄40.031, respectively) but was unrelated to serum androgens (p1⁄40.08). Mice consuming Zetia diet had lower rates of intracystic adenocarcinoma at 2 and 3 months of age (0% vs. 14% and 30% vs. 44%, respectively). CONCLUSIONS: Using a PTEN-deficient transgenic mouse model of prostate cancer, we found that serum cholesterol reduction lowered intraprostatic androgen concentrations and slowed prostate cancer progression, supporting a potentially important role for cholesterol in prostate cancer. This study may provide new insight into the use of cholesterol-lowering interventions for prostate cancer prevention and treatment.