title: The estrogen receptor as a mediator of the pathological actions of cholesterol in breast cancer.
abstract: 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 hyper-cholesterolemia 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.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine , Durham, NC , USA.
authors.forename: D P
authors.initials: DP
authors.lastname: McDonnell
authors.forename: C-Y
authors.initials: CY
authors.lastname: Chang
authors.forename: E R
authors.initials: ER
authors.lastname: Nelson
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000276:immunology; D001943:Breast Neoplasms / Q000453:epidemiology / Q000209:etiology* / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000097:blood / Q000633:toxicity*; D004195:Disease Models, Animal; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D006801:Humans; D006888:Hydroxycholesterols / Q000097:blood / Q000138:chemical synthesis; D006949:Hyperlipidemias / Q000150:complications / Q000188:drug therapy; D015994:Incidence; D009364:Neoplasm Recurrence, Local; D009765:Obesity / Q000150:complications; D019899:Paracrine Communication / Q000276:immunology; D011960:Receptors, Estrogen / Q000378:metabolism*; D012307:Risk Factors; D020845:Selective Estrogen Receptor Modulators / Q000378:metabolism
chemical_list: D002791:Cholesterol, Dietary; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D006888:Hydroxycholesterols; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; C076996:27-hydroxycholesterol; D002784:Cholesterol
keywords: 27-HYDROXYCHOLESTEROL; BREAST CANCER; CYP27A1; SERM; STATINS