The impact of 27-hydroxycholesterol on endometrial cancer proliferation

Douglas A. Gibson, Frances Collins, Fiona L. Cousins, Arantza Esnal Zufiaurre, Philippa T.K. Saunders

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11 Citations (Scopus)

Abstract

Endometrial cancer (EC) is the most common gynaecological malignancy. Obesity is a major risk factor for EC and is associated with elevated cholesterol. 27-hydroxycholesterol (27HC) is a cholesterol metabolite that functions as an endogenous agonist for Liver X receptor (LXR) and a selective oestrogen receptor modulator (SERM). Exposure to oestrogenic ligands increases risk of developing EC; however, the impact of 27HC on EC is unknown. Samples of stage 1 EC (n = 126) were collected from postmenopausal women undergoing hysterectomy. Expression of LXRs (NR1H3, LXRα; NR1H2, LXRβ) and enzymes required for the synthesis (CYP27A1) or breakdown (CYP7B1) of 27HC were detected in all grades of EC. Cell lines originating from well-, moderate- and poorly-differentiated ECs (Ishikawa, RL95, MFE 280 respectively) were used to assess the impact of 27HC or the LXR agonist GW3965 on proliferation or expression of a luciferase reporter gene under the control of LXR- or ER-dependent promoters (LXRE, ERE). Incubation with 27HC or GW3965 increased transcription via LXRE in Ishikawa, RL95 and MFE 280 cells (P < 0.01). 27HC selectively activated ER-dependent transcription (P < 0.001) in Ishikawa cells and promoted proliferation of both Ishikawa and RL95 cells (P < 0.001). In MFE 280 cells, 27HC did not alter proliferation but selective targeting of LXR with GW3965 significantly reduced cell proliferation (P < 0.0001). These novel results suggest that 27HC can contribute to risk of EC by promoting proliferation of endometrial cancer epithelial cells and highlight LXR as a potential therapeutic target in the treatment of advanced disease.

Original languageEnglish
Pages (from-to)381-391
Number of pages11
JournalEndocrine-Related Cancer
Volume25
Issue number4
DOIs
Publication statusPublished - 1 Apr 2018
Externally publishedYes

Keywords

  • 27-hydroxycholesterol
  • Endometrial cancer
  • ER
  • LXR
  • Proliferation

Cite this

Gibson, D. A., Collins, F., Cousins, F. L., Esnal Zufiaurre, A., & Saunders, P. T. K. (2018). The impact of 27-hydroxycholesterol on endometrial cancer proliferation. Endocrine-Related Cancer, 25(4), 381-391. https://doi.org/10.1530/ERC-17-0449