27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology.

Abstract

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.

• Authors: Erik R Nelson, Suzanne E Wardell, Jeff S Jasper, Sunghee Park, Sunil Suchindran, Matthew K Howe, Nicole J Carver, Ruchita V Pillai, Patrick M Sullivan, Varun Sondhi, Michihisa Umetani, Joseph Geradts, Donald P McDonnell
• Journal: Science (New York, N.Y.) (Science) Vol. 342 Issue 6162 Pg. 1094-8 (Nov 29 2013) ISSN: 1095-9203 [Electronic] United States
• PMID: 24288332 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Hydroxycholesterols
• 27-hydroxycholesterol
• CYP27A1 protein, human
• Cholestanetriol 26-Monooxygenase

Topics

• Animals
• Breast Neoplasms (blood, metabolism, pathology)
• Cell Line, Tumor
• Cholestanetriol 26-Monooxygenase (antagonists & inhibitors, metabolism)
• Disease Models, Animal
• Female
• Humans
• Hydroxycholesterols (antagonists & inhibitors, blood, metabolism)
• Hypercholesterolemia (blood, metabolism)
• Lung Neoplasms (secondary)
• Mice
• Tumor Cells, Cultured