Abstract 3698: Inhibition of cholesterol uptake with ezetimibe reduces intra-tumoral testosterone levels and slows tumor growth in transgenic mouse models of prostate cancer.

Introduction: Western countries have 6 fold higher incidence of prostate cancer (PC). Dietary composition, in addition to other factors, may contribute to this geographic disparity. Cholesterol, the precursor for de novo steroid hormone synthesis, has been hypothesized to promote PC growth via multiple pathways including intratumoral steroidogenesis. While lowering serum cholesterol slows xenograft PC growth, this has not been tested in transgenic models, which allow testing of PC prevention as well as modulating PC growth in an orthotopic position. We determined the effect of cholesterol uptake inhibition, using ezetimibe, on PC growth in Hi-Myc and PTEN transgenic mice. Methods: We randomized 50 c-myc/wt (Hi-Myc) mice and 30 PTEN loxP/loxP -Cre + (PTEN) to one of two diets: high fat high cholesterol (HFHC; 40% fat, 17% protein, 43% carbohydrate, 1.25% cholesterol), or HFHC with ezetimibe (30 mg/kg food) (HFHC+Z). Mice were fed ad libitum starting right after weaning and body weights measured twice weekly. Prostate, liver, spleen, adipose tissue and serum were harvested from Hi-Myc and PTEN mice at age 6 and 4 months, respectively. Serum cholesterol and testosterone (T) and tumor T were measured in Hi-Myc mice and are ongoing in PTEN mice. Results: In Hi-Myc mice, body weights were significantly greater in the HFHC+Z group at sacrifice, relative to the HFHC group (p=0.04), but there were no differences in prostate weight between groups with adjustment for body weight (p=0.84). In PTEN mice, there was no difference in body weights between groups, but prostate weight was significantly lower in the HFHC+Z group, relative to the HFHC group (p=0.046). In Hi-Myc mice, while serum T levels did not vary between groups (p=0.93), tumor T, dihydrotestosterone (DHT) and androstenedione concentrations were significantly reduced in the HFHC+Z group, relative to the HFHC group (p=0.01, p=0.01, p=0.006, respectively). Discussion: Reduction of serum cholesterol levels using cholesterol uptake inhibitor, ezetimibe, significantly reduced prostate weight in PTEN mice consuming a HFHC diet. Furthermore, supplementation of the HFHC diet with ezetimibe significantly reduced tumor concentrations of T, DHT and androstenedione in Hi-Myc mice, although there was no effect on prostate weight. These findings highlight a potentially critical role for cholesterol in PC progression by providing evidence that reduction of hypercholesterolemia may reduce intratumoral de novo steroidogenesis and slow PC growth. This study may provide new insight into the use of cholesterol-lowering drugs for PC prevention and treatment. Citation Format: Emma H. Allott, Elizabeth M. Masko, Alexa Choy, Alexis R. Gaines, Keith R. Solomon, Salvatore V. Pizzo, Stephen J. Freedland. Inhibition of cholesterol uptake with ezetimibe reduces intra-tumoral testosterone levels and slows tumor growth in transgenic mouse models of prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3698. doi:10.1158/1538-7445.AM2013-3698