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

Author

Listed:
  • 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
    Durham Veterans Affairs Medical Center)

  • 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
    University of Illinois Cancer Center
    University of Illinois at Urbana-Champaign)

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.

Suggested Citation

  • 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 & Jongso, 2017. "The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00910-z
    DOI: 10.1038/s41467-017-00910-z
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    Cited by:

    1. Yi-Yu Chen & Jing-Yu Ge & Si-Yuan Zhu & Zhi-Ming Shao & Ke-Da Yu, 2022. "Copy number amplification of ENSA promotes the progression of triple-negative breast cancer via cholesterol biosynthesis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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