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Cited by 427Cancer, Lipids, and MetabolismImmune cells in cancerCholesterol and Lipid Metabolism

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

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Baek, Amy E., Yu, Yen-Rei A., He, Sisi, Wardell, Suzanne E., Chang, Ching-Yi, Kwon, Sanghoon, Pillai, Ruchita V., McDowell, Hannah B. +7 more·2017·Nature Communications
DOI 10.1038/s41467-017-00910-zPMC PMC5636879
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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.

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  • 27-hydroxycholesterol works through liver x receptors in myeloid immune cells to suppress T cell proliferation and function, stimulate secretion of pro-tumor extracellular vesicles, and promote tumor and metastatic growth.

    “An oxysterol metabolite of cholesterol, 27-hydroxycholesterol, was found to work through the liver x receptors in myeloid immune cells to robustly suppress T cell proliferation and function, and stimulate the secretion of pro-tumor extracellular vesicles, ultimately promoting the growth of tumors and metastatic lesions (17, 20–23).”

    From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [17]

    The Results and Discussion report that 27-hydroxycholesterol promotes metastasis through myeloid cells, particularly neutrophils, and is associated with reduced cytotoxic CD8+ T-cell activity. The Discussion links the neutrophil-mediated effect to CXCR2; although it describes 27-hydroxycholesterol as an LXR agonist, it does not establish LXR signaling in myeloid cells as this mechanism. Our copy also does not support the claimed secretion of pro-tumor extracellular vesicles. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
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.
Affiliations
  • University of Illinois Urbana-Champaign (US)
  • Duke University (US)
Corresponding author
Nelson, Erik R.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2017-10-11
Volume
8
Issue
1
Pages
864-864
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-017-00910-z
PMC
PMC5636879
OpenAlex
W2763053047
Cited by
427
References
5
Citations by year
2026: 49 · 2025: 52 · 2024: 56 · 2023: 43 · 2022: 63 · 2021: 61 · 2020: 46 · 2019: 40 · 2018: 15 · 2017: 2
FWCI
9.46
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (DK48807)
  • National Cancer Institute (R00CA172357)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK062777, R01DK048807, R01DK095842)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
27-hydroxycholesterol, breast cancer metastasis, oxysterols, CYP27A1, hypercholesterolemia, high-fat diet, obesity, myeloid cells, neutrophils, γδ T cells, CD8+ T cells, immune cell function, statins, cholesterol metabolism
MeSH terms
Animals, Breast Neoplasms, Carcinoma, Cholesterol, Dietary, Female, Humans, Hydroxycholesterols, Mice, Inbred C57BL, Neoplasm Metastasis, Obesity, Myeloid Cells, Cell Line, Tumor, Mice

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