Endocrine Abstracts

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 estrogen receptor modulator (SERM). Exposure to estrogenic 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 post-menopausal women undergoing total abdominal hysterectomy according to a method approved by the local institutional ethics committee. Expression of LXRs (NR1H3, LXRα; NR1H2, LXRβ) and enzymes required for the synthesis (CYP27A1) or breakdown (CYP7B1) of 27HC was assessed in all grades of EC. LXRα and LXRβ expression was detected in EC but did not change with grade. Expression of CYP7B1 decreased with disease severity (P<0.05) consistent with an association between increased bioavailability of 27HC and progression of EC.

The impact of 27HC or the LXR agonist GW3965 on cell proliferation or expression of an LXR- or ER-dependent luciferase reporter gene was assessed in cell lines originating from well-, moderate- and poorly-differentiated endometrial cancers (Ishikawa, RL95, and MFE 280 respectively). Incubation with 27HC or GW3965 increased transcription via LXRE in Ishikawa, RL95 and MFE 280 cells (P<0.01). 27HC selectively increased ERE reporter activity in Ishikawa cells (P<0.001) and promoted proliferation of both Ishikawa and RL95 cells (P<0.001). Selective targeting of LXR with GW3965 significantly reduced cell proliferation of RL95 and MFE280 cells (P<0.0001).

Altered cholesterol metabolism and exposure to 27HC may contribute to endometrial cancer risk by altering cell proliferation. These novel results suggest that 27HC can promote proliferation of endometrial cancer epithelial cells and highlight LXR as a potential therapeutic target in the treatment of advanced disease.