27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology

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

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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.

Original languageEnglish (US)
Pages (from-to)1094-1098
Number of pages5
JournalScience
Volume342
Issue number6162
DOIs
StatePublished - Jan 1 2013

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Cite this

Nelson, E. R., Wardell, S. E., Jasper, J. S., Park, S., Suchindran, S., Howe, M. K., Carver, N. J., Pillai, R. V., Sullivan, P. M., Sondhi, V., Umetani, M., Geradts, J., & McDonnell, D. P. (2013). 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. Science, 342(6162), 1094-1098. https://doi.org/10.1126/science.1241908