RT Journal Article
SR Electronic
T1 27-Hydroxycholesterol Links Hypercholesterolemia and Breast Cancer Pathophysiology
JF Science
JO Science
FD American Association for the Advancement of Science
SP 1094
OP 1098
DO 10.1126/science.1241908
VO 342
IS 6162
A1 Nelson, Erik R.
A1 Wardell, Suzanne E.
A1 Jasper, Jeff S.
A1 Park, Sunghee
A1 Suchindran, Sunil
A1 Howe, Matthew K.
A1 Carver, Nicole J.
A1 Pillai, Ruchita V.
A1 Sullivan, Patrick M.
A1 Sondhi, Varun
A1 Umetani, Michihisa
A1 Geradts, Joseph
A1 McDonnell, Donald P.
YR 2013
UL http://science.sciencemag.org/content/342/6162/1094.abstract
AB Obesity and high cholesterol levels are associated with an increased risk of breast cancer in post-menopausal women. Nelson et al. (p. 1094) found that a specific metabolite of cholesterol, 27-hydroxycholesterol (27HC), promoted tumor growth and metastasis in mouse models of mammary cancer by serving as a partial agonist for the estrogen receptor and the liver X receptor. The most aggressive human breast cancers were found to express the highest level of the enzyme that converts cholesterol to 27HC, suggesting that 27HC produced within tumors (in addition to circulating 27HC) may contribute to tumorigenesis. Hypercholesterolemia is a risk factor for estrogen receptor (ER)–positive breast cancers and is associated with a decreased response of tumors to endocrine therapies. Here, we show that 27-hydroxycholesterol (27HC), a primary metabolite of cholesterol and an ER and liver X receptor (LXR) ligand, increases ER-dependent growth and LXR-dependent metastasis in mouse models of breast cancer. The effects of cholesterol on tumor pathology required its conversion to 27HC by the cytochrome P450 oxidase CYP27A1 and were attenuated by treatment with CYP27A1 inhibitors. In human breast cancer specimens, CYP27A1 expression levels correlated with tumor grade. In high-grade tumors, both tumor cells and tumor-associated macrophages exhibited high expression levels of the enzyme. Thus, lowering circulating cholesterol levels or interfering with its conversion to 27HC may be a useful strategy to prevent and/or treat breast cancer.