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

  • Nat Commun. 2017 Oct 11;8(1):864. doi: 10.1038/s41467-017-00910-z.
Amy E Baek  1 ,  Yen-Rei A Yu  2 ,  Sisi He  1 ,  Suzanne E Wardell  3 ,  Ching-Yi Chang  3 ,  Sanghoon Kwon  1 ,  Ruchita V Pillai  3 ,  Hannah B McDowell  1 ,  J Will Thompson  4 ,  Laura G Dubois  4 ,  Patrick M Sullivan  5  6 ,  Jongsook K Kemper  1 ,  Michael D Gunn  2 ,  Donald P McDonnell  3 ,  Erik R Nelson  7  8  9
Affiliations
  • 1. Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, 407S Goodwin Avenue (MC-114), Urbana, IL, 61801, USA.
  • 2. Department of Medicine, Division of Cardiology, Duke University School of Medicine, 346 Sands Building, Durham, NC, 27710, USA.
  • 3. Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Box 3813, Durham, NC, 27710, USA.
  • 4. Proteomics and Metabolomics Shared Resources, Duke University School of Medicine, B02 Levine Science Research Center, 450 Science Drive, Durham, NC, 27708, USA.
  • 5. Department of Medicine, Duke University School of Medicine, Durham, 27710, NC, USA.
  • 6. Geriatric Research, Education and Clinical Center, Durham Veterans Affairs Medical Center, 508 Fulton Street, Durham, NC, 27705, USA.
  • 7. Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, 407S Goodwin Avenue (MC-114), Urbana, IL, 61801, USA. [email protected].
  • 8. University of Illinois Cancer Center, Chicago, IL, 60612, USA. [email protected].
  • 9. Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA. [email protected].
PMID: 29021522 DOI: 10.1038/s41467-017-00910-z
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.High Cholesterol is a risk factor for breast Cancer recurrence. Here the authors show that Cholesterol promotes breast Cancer metastasis via its metabolite 27-hydroxycholesterol (27HC) that acts on immune myeloid cells residing at the distal metastatic sites, thus promoting an immune suppressive environment.

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