Host CYP27A1 expression is essential for ovarian cancer progression

Sisi He, Liqian Ma, Amy E. Baek, Anna Vardanyan, Varsha Vembar, Joy J. Chen, Adam T. Nelson, Joanna E. Burdette, Erik R. Nelson

Research output: Contribution to journalArticle

Abstract

There is an urgent need for more effective strategies to treat ovarian cancer. Elevated cholesterol levels are associated with a decreased progression-free survival time (PFS) while statins are protective. 27-Hydroxycholesterol (27HC), a primary metabolite of cholesterol, has been shown to modulate the activities of the estrogen receptors (ERs) and liver x receptors (LXRs) providing a potential mechanistic link between cholesterol and ovarian cancer progression. We found that high expression of CYP27A1, the enzyme responsible for the synthesis of 27HC, was associated with decreased PFS, while high expression of CYP7B1, responsible for 27HC catabolism, was associated with increased PFS. However, 27HC decreased the cellular proliferation of various ovarian cancer cell lines in an LXR-dependent manner. Intriguingly, ID8 grafts were unable to effectively establish in CYP27A1−/− mice, indicating involvement of the host environment. Tumors from mice treated with 27HC had altered myeloid cell composition, and cells from the marrow stem cell lineage were found to be responsible for the effects in CYP27A1−/− mice. While inhibition of CYP27A1 or immune checkpoint did not significantly alter tumor size, their combination did, thereby highlighting this axis as a therapeutic target.

Original languageEnglish (US)
Pages (from-to)659-675
Number of pages17
JournalEndocrine-Related Cancer
Volume26
Issue number7
DOIs
StatePublished - Jan 1 2019

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Keywords

  • 27-hydroxycholesterol
  • Cholesterol
  • Myeloid-derived suppressor cells
  • Ovarian cancer
  • Tumor microenvironment

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Oncology
  • Endocrinology
  • Cancer Research

Cite this

He, S., Ma, L., Baek, A. E., Vardanyan, A., Vembar, V., Chen, J. J., Nelson, A. T., Burdette, J. E., & Nelson, E. R. (2019). Host CYP27A1 expression is essential for ovarian cancer progression. Endocrine-Related Cancer, 26(7), 659-675. https://doi.org/10.1530/ERC-18-0572