The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells

Amy E. Baek, Yen Rei A. Yu, Sisi He, Suzanne E. Wardell, Ching Yi Chang, Sanghoon Kwon, Ruchita V. Pillai, Hannah B. McDowell, J. Will Thompson, Laura G. Dubois, Patrick M. Sullivan, Jongsook K. Kemper, Michael D. Gunn, Donald P. McDonnell, Erik R. Nelson

Research output: Contribution to journalArticle

Abstract

Obesity and elevated circulating cholesterol are risk factors for breast cancer recurrence, while the use of statins, cholesterol biosynthesis inhibitors widely used for treating hypercholesterolemia, is associated with improved disease-free survival. Here, we show that cholesterol mediates the metastatic effects of a high-fat diet via its oxysterol metabolite, 27-hydroxycholesterol. Ablation or inhibition of CYP27A1, the enzyme responsible for the rate-limiting step in 27-hydroxycholesterol biosynthesis, significantly reduces metastasis in relevant animal models of cancer. The robust effects of 27-hydroxycholesterol on metastasis requires myeloid immune cell function, and it was found that this oxysterol increases the number of polymorphonuclear-neutrophils and γδ-T cells at distal metastatic sites. The pro-metastatic actions of 27-hydroxycholesterol requires both polymorphonuclear-neutrophils and γδ-T cells, and 27-hydroxycholesterol treatment results in a decreased number of cytotoxic CD8+T lymphocytes. Therefore, through its actions on γδ-T cells and polymorphonuclear-neutrophils, 27-hydroxycholesterol functions as a biochemical mediator of the metastatic effects of hypercholesterolemia.

Original languageEnglish (US)
Article number864
JournalNature communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Baek, A. E., Yu, Y. R. A., He, S., Wardell, S. E., Chang, C. Y., Kwon, S., Pillai, R. V., McDowell, H. B., Thompson, J. W., Dubois, L. G., Sullivan, P. M., Kemper, J. K., Gunn, M. D., McDonnell, D. P., & Nelson, E. R. (2017). The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells. Nature communications, 8(1), [864]. https://doi.org/10.1038/s41467-017-00910-z