Abstract 173: Hypercholesterolemia induces angiogenesis and causes accelerated growth of breast tumors in vivo.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: While many risk factors for breast cancer (BC) such as family history and age have been firmly established, evidence suggests that dietary factors may also play a role in BC. Studies have linked intake of saturated fat as well as metabolic syndrome to an increased prevalence of BC. A common feature shared by metabolic syndrome and a typical American diet is a high level of circulating cholesterol, however a number of epidemiological reports investigating the relationship between high cholesterol levels, cholesterol lowering drugs and BC are conflicting. To determine the relationship between dietary cholesterol and BC in vivo, we modeled this complex condition in a well controlled animal model that utilized an innovative isocaloric diet. We hypothesized that hypercholesterolemia promotes BC progression while hypocholesterolemia has the opposite effect and retards BC progression. Methods: Female SCID mice were fed a low fat/no cholesterol (LFNC) diet for 2 weeks and then randomized to 4 diet groups with calorie set at 21.2 Kcal/day. These isocaloric diets consisted of a LFNC diet with or without ezetimibe (a drug that specifically blocks cholesterol uptake in the gut, thereby lowering serum cholesterol) and a high fat/high cholesterol (HFHC) diet with and without ezetimibe. Significant differences in serum cholesterol level between groups were achieved and maintained throughout the study. Mice were then implanted orthotopically with MDA-MB-231 BC cells into the 4th mammary fat pad and tumor growth was monitored every 3 days until sacrifice when tumors were harvested. Results: No differences in tumor take were observed (>95% for all groups). Tumors from animals fed the HFHC diet exhibited the fastest progression. While significant differences in serum cholesterol were observed between the diet groups, no differences were observed in the intratumoral cholesterol levels. To determine the underlying mechanism of cholesterol-induced tumor progression, we assessed tumor proliferation, apoptosis and angiogenesis. Ki67 analyses of tumor proliferation demonstrated a significantly greater percentage of proliferating cells in tumor from mice fed the HFHC diet (48%) compared to animals on the HFHC diet with ezetimibe or the LFNC diet with and without ezetimibe (32%, 33% and 30% respectively). Tumors from hypercholesterolemic animals displayed significantly less apoptosis, as determined by percentage of TUNEL positive cells (39%), compared to the other diet groups (49%, 52% and 58%). Finally, when tumor angiogenesis was evaluated by CD31 staining and microvessel density was quantified, tumors from HFHC mice had vessel areas that were 70% greater, on average, compared to tumors from the other groups. Conclusion: These results demonstrate that hypercholesterolemia induces angiogenesis and accelerates breast tumor growth in vivo. Supported by the Breast Cancer Research Foundation and NIH P01 [CA045548][1] Citation Format: Christine M. Coticchia, Kristine Pelton, Adam S. Curatolo, David Zurakowski, Carl P. Schaffner, Keith R. Solomon, Marsha A. Moses. Hypercholesterolemia induces angiogenesis and causes accelerated growth of breast tumors in vivo . [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 173. doi:10.1158/1538-7445.AM2013-173 [1]: /lookup/external-ref?link_type=GEN&access_num=CA045548&atom=%2Fcanres%2F73%2F8_Supplement%2F173.atom