The impact of 27-hydroxycholesterol on endometrial cancer proliferation

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.

27-hydroxycholesterol decreases cell proliferation in colon cancer cell lines

“…Previous studies showed that, E1, but not E2, significantly decreases proliferation when added exogenously to the colonic epithelial cell line, SW620 cells [51]. In different cell models however, 27-OHC has been shown to increase proliferation in endometrium through ER and LXR pathways [52]. Although we show a decrease in cell proliferation, the cellular mechanisms by which 27-OHC affects proliferation is yet to be determined.…”

Association between metabolic syndrome and endometrial cancer risk: a systematic review and meta-analysis of observational studies

“…Insulin can activate the phosphoinositide 3kinase/protein kinase B or mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway by binding to insulin receptor/insulin-like growth factor-1 receptor, thereby promoting epithelialmesenchymal transition and increasing the proliferation and invasion of EC cells [27]. Furthermore, a recent study has reported that cholesterol can activate the transcriptional activity of EC cells and promote the proliferation of EC cells [28].…”

Obesity and Cancer: 27-Hydroxycholesterol, the Missing Link

“…Moreover, using kinase inhibitors, we demonstrated that the effect of 27HC was mediated by the PI3K-Akt signaling pathway [ 26 ]. Another group working on endometrial cancer, the most common gynecological malignancy, showed that 27HC contributes to the risk of endometrial cancer by promoting the proliferation of endometrial cancer epithelial cells and also the activation of ER-dependent transcription in well-differentiated endometrial cancer cells [ 91 ]. A recent study demonstrated the effects of 27HC on colorectal cancer, the third most diagnosed cancer in the western world [ 91 ].…”

“…Another group working on endometrial cancer, the most common gynecological malignancy, showed that 27HC contributes to the risk of endometrial cancer by promoting the proliferation of endometrial cancer epithelial cells and also the activation of ER-dependent transcription in well-differentiated endometrial cancer cells [ 91 ]. A recent study demonstrated the effects of 27HC on colorectal cancer, the third most diagnosed cancer in the western world [ 91 ]. Treating Caco2 and SW620 colon cancer cells with 27HC led to a reduced cellular proliferation.…”