Hypercholesterolemia Promotes Prostate Cancer Pc-3 Metastases In Orthotopic Xenograft Mice

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Hypercholesterolemia has been proposed as a potential risk factor for advanced prostate cancer, and use of cholesterol-lowering drugs, statins, inversely correlates with advanced prostate cancer risk. Hypercholesterolemia increases growth of androgen-sensitive LNCaP xenograft in vivo, potentially via androgen signaling. The aim of this study was to determine if hypercholesterolemia affects castration-resistant prostate tumor progression using an androgen receptor-negative prostate cancer cell line PC-3. Compared to control media, cholesterol-deficient media reduced PC-3 proliferation, migration and anchorage-independent growth in vitro. While adding cholesterol did not significantly increase proliferation or anchorage-independent growth, cholesterol replacement in cholesterol-deficient media significantly increased PC-3 transmigration. In order to determine the in vivo effect, mice were randomly assigned to normal or hypercholesterolemic, isocaloric diet groups (N=14 and 15, respectively). After two weeks, hypercholesterolemic diet significantly increased circulating cholesterol but did not increase body weight. PC-3 cells stably expressing luciferase were orthotopically injected into the dorsolateral prostate. Tumor progression and metastases were monitored by in vivo and ex vivo optical bioluminescence imaging for 6 weeks. Strikingly, the results show that diet-induced hypercholesterolemia accelerated tumor metastases to lymph nodes, lung, proximal and distant bones without significantly affecting primary tumor growth. The metastases were confirmed histopathologcally. Hypercholesterolemia was not associated with elevated weight or circulating testosterone. This is the first study to directly demonstrate a causal relationship between hypercholesterolemia and prostate tumor metastases mediated through androgen-independent mechanisms, highlighting the potential clinical benefit of cholesterol lowering therapy such as statins in advanced, castration-resistant, prostate cancer patients. Citation Format: Hyeongsun Moon, Laura Sharpe, Eunju Choi, Helle Bielefeldt-Ohmann, Zeyad Nassar, Marie-Odile Parat, Mathias Francois, C Soon Lee, Andrew Brown, Pamela Russell, Kerry Inder, Michelle Hill. Hypercholesterolemia promotes prostate cancer PC-3 metastases in orthotopic xenograft mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4950. doi:10.1158/1538-7445.AM2014-4950