期刊
CLIMACTERIC
卷 17, 期 -, 页码 60-65出版社
INFORMA HEALTHCARE
DOI: 10.3109/13697137.2014.966949
关键词
SERM; 27-HYDROXYCHOLESTEROL; CYP27A1; BREAST CANCER; STATINS
资金
- Department of Defense Idea Expansion Award [W81XWH-13-1-0366]
- National Cancer Institute of the National Institutes of Health [K99CA172357]
- National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health [R37DK048807]
Despite increased survivorship among patients, breast cancer remains the most common cancer among women and is the second leading cause of cancer death in women. The magnitude of this problem provides a strong impetus for new chemopreventative strategies and/or lifestyle changes that reduce cancer incidence. It is of significance, therefore, that several studies positively correlate obesity to the development of breast cancer. Importantly, obesity is also highly associated with elevated cholesterol, and cholesterol itself is a risk factor for breast cancer. Furthermore, patients taking statins demonstrate a lower breast cancer incidence and decreased recurrence. The recent observation that 27-hydroxycholesterol (27HC) is produced in a stoichiometric manner from cholesterol, together with our recent demonstration that it exerts partial agonist activity on both the estrogen and liver X receptors, suggested a potential mechanistic link between hypercholesterolemia and breast cancer incidence. Using genetic and pharmacological approaches, we have recently shown that elevation of circulating 27HC significantly increases tumor growth and metastasis in murine models of breast cancer. Further, we have demonstrated in appropriate animal models that the impact of high-fat diet on tumor pathogenesis can be mitigated by statins or by small molecule inhibitors of CYP27A1. These findings suggest that pharmacological or dietary modifications that lower total cholesterol, and by inference 27HC, are likely to reduce the impact of obesity/metabolic syndrome on breast cancer incidence.
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