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 and Erik R. Nelson ()
Additional contact information
Amy E. Baek: University of Illinois at Urbana-Champaign
Yen-Rei A. Yu: Duke University School of Medicine
Sisi He: University of Illinois at Urbana-Champaign
Suzanne E. Wardell: Duke University School of Medicine
Ching-Yi Chang: Duke University School of Medicine
Sanghoon Kwon: University of Illinois at Urbana-Champaign
Ruchita V. Pillai: Duke University School of Medicine
Hannah B. McDowell: University of Illinois at Urbana-Champaign
J. Will Thompson: Duke University School of Medicine
Laura G. Dubois: Duke University School of Medicine
Patrick M. Sullivan: Duke University School of Medicine
Jongsook K. Kemper: University of Illinois at Urbana-Champaign
Michael D. Gunn: Department of Medicine, Division of Cardiology, Duke University School of Medicine, 346 Sands Building
Donald P. McDonnell: Duke University School of Medicine
Erik R. Nelson: University of Illinois at Urbana-Champaign

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00910-z

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