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

doi:10.1038/s41467-017-00910-z

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 journal › Article › peer-review

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 language	English (US)
Article number	864
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-00910-z
State	Published - Dec 1 2017

ASJC Scopus subject areas

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

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10.1038/s41467-017-00910-z

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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

Baek, AE, Yu, YRA, He, S, Wardell, SE, Chang, CY, Kwon, S, Pillai, RV, McDowell, HB, Thompson, JW, Dubois, LG, Sullivan, PM, Kemper, JK, Gunn, MD, McDonnell, DP & Nelson, ER 2017, 'The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells', Nature communications, vol. 8, no. 1, 864. https://doi.org/10.1038/s41467-017-00910-z

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title = "The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells",

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.",

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

note = "Funding Information: Research reported in this publication was supported by the National Institutes of Health under award numbers R00CA172357 (E.R.N.), K99CA172357 (E.R.N.) and DK48807 (D.P.M.), and a Susan G. Komen PDF16377624 (A.E.B.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Susan G. Komen. We would like to thank Savannah B. Hipkins for her technical assistance, and Sarah Y. Adams for serving as a Breast Cancer Advocate on this project. Publisher Copyright: {\textcopyright} 2017 The Author(s).",

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doi = "10.1038/s41467-017-00910-z",

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T1 - The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells

AU - Baek, Amy E.

AU - Yu, Yen Rei A.

AU - He, Sisi

AU - Wardell, Suzanne E.

AU - Chang, Ching Yi

AU - Kwon, Sanghoon

AU - Pillai, Ruchita V.

AU - McDowell, Hannah B.

AU - Thompson, J. Will

AU - Dubois, Laura G.

AU - Sullivan, Patrick M.

AU - Kemper, Jongsook K.

AU - Gunn, Michael D.

AU - McDonnell, Donald P.

AU - Nelson, Erik R.

N1 - Funding Information: Research reported in this publication was supported by the National Institutes of Health under award numbers R00CA172357 (E.R.N.), K99CA172357 (E.R.N.) and DK48807 (D.P.M.), and a Susan G. Komen PDF16377624 (A.E.B.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Susan G. Komen. We would like to thank Savannah B. Hipkins for her technical assistance, and Sarah Y. Adams for serving as a Breast Cancer Advocate on this project. Publisher Copyright: © 2017 The Author(s).

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

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ER -

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

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