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

Research output: Contribution to journalArticle

311 Citations (Scopus)

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 - 2013

Fingerprint

Hypercholesterolemia
Breast Neoplasms
Estrogen Receptors
Neoplasms
Cholesterol
Electron Transport Complex IV
Cytochrome P-450 Enzyme System
27-hydroxycholesterol
Breast Cancer
Macrophages
Pathology
Neoplasm Metastasis
Ligands
Estrogen
Enzymes
Growth

ASJC Scopus subject areas

  • General
  • History and Philosophy of Science
  • Medicine(all)

Cite this

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

27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. / Nelson, Erik R.; Wardell, Suzanne E.; Jasper, Jeff S.; Park, Sunghee; Suchindran, Sunil; Howe, Matthew K.; Carver, Nicole J.; Pillai, Ruchita V.; Sullivan, Patrick M.; Sondhi, Varun; Umetani, Michihisa; Geradts, Joseph; McDonnell, Donald P.

In: Science, Vol. 342, No. 6162, 2013, p. 1094-1098.

Research output: Contribution to journalArticle

Nelson, ER, Wardell, SE, Jasper, JS, Park, S, Suchindran, S, Howe, MK, Carver, NJ, Pillai, RV, Sullivan, PM, Sondhi, V, Umetani, M, Geradts, J & McDonnell, DP 2013, '27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology', Science, vol. 342, no. 6162, pp. 1094-1098. https://doi.org/10.1126/science.1241908
Nelson ER, Wardell SE, Jasper JS, Park S, Suchindran S, Howe MK et al. 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. Science. 2013;342(6162):1094-1098. https://doi.org/10.1126/science.1241908
Nelson, Erik R. ; Wardell, Suzanne E. ; Jasper, Jeff S. ; Park, Sunghee ; Suchindran, Sunil ; Howe, Matthew K. ; Carver, Nicole J. ; Pillai, Ruchita V. ; Sullivan, Patrick M. ; Sondhi, Varun ; Umetani, Michihisa ; Geradts, Joseph ; McDonnell, Donald P. / 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. In: Science. 2013 ; Vol. 342, No. 6162. pp. 1094-1098.
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