Expression of oestrogen receptors, ERα, ERβ, and ERβ variants, in endometrial cancers and evidence that prostaglandin F may play a role in regulating expression of ERα

Frances Collins,Sheila Macpherson,Richard A Anderson,Vincent Bombail,Philippa Tk Saunders,Alistair Rw Williams,Pamela Brown,Henry N Jabbour

doi:10.1186/1471-2407-9-330

Abstract

BackgroundEndometrial cancer is the most common gynaecological malignancy; risk factors include exposure to oestrogens and high body mass index. Expression of enzymes involved in biosynthesis of oestrogens and prostaglandins (PG) is often higher in endometrial cancers when compared with levels detected in normal endometrium. Oestrogens bind one of two receptors (ERα and ERβ) encoded by separate genes. The full-length receptors function as ligand-activated transcription factors; splice variant isoforms of ERβ lacking a ligand-binding domain have also been described. PGs act in an autocrine or paracrine manner by binding to specific G-protein coupled receptors.MethodsWe compared expression of ERs, progesterone receptor (PR) and cyclooxygenase-2 (COX-2) in stage 1 endometrial adenocarcinomas graded as well (G1), moderately (G2) or poorly (G3) differentiated (n ≥ 10 each group) using qRTPCR, single and double immunohistochemistry. We used endometrial adenocarcinoma cell lines to investigate the impact of PGF2α on expression of ERs and PR.ResultsFull length ERβ (ERβ1) and two ERβ variants (ERβ2, ERβ5) were expressed in endometrial cancers regardless of grade and the proteins were immunolocalised to the nuclei of cells in both epithelial and stromal compartments. Immunoexpression of COX-2 was most intense in cells that were ERαneg/low. Expression of PR in endometrial adenocarcinoma (Ishikawa) cell lines and tissues broadly paralleled that of ERα. Treatment of adenocarcinoma cells with PGF2α reduced expression of ERα but had no impact on ERβ1. Cells incubated with PGF2α were unable to increase expression of PR mRNA when they were incubated with E2.ConclusionWe have demonstrated that ERβ5 protein is expressed in stage 1 endometrial adenocarcinomas. Expression of three ERβ variants, including the full-length protein is not grade-dependent and most cells in poorly differentiated cancers are ERβpos/ERαneg. We found evidence of a link between COX-2, its product PGF2α, and expression of ERα and PR that sheds new light on the cross talk between steroid and PG signalling pathways in this disease.

Highlights

Endometrial cancer is the most common gynaecological malignancy; risk factors include exposure to oestrogens and high body mass index
Patients and tissue collection Endometrial adenocarcinoma tissue was collected from post-menopausal women undergoing total abdominal hysterectomy who had been previously diagnosed to have endometrioid adenocarcinoma of the endometrium; they had received no treatment before surgery
Expression of oestrogen receptors in stage 1 endometrial cancers The amount of ERα mRNA was significantly lower in poorly differentiated cancers compared with cancers graded as well or moderately differentiated (Figure 1A)

Summary

Introduction

Endometrial cancer is the most common gynaecological malignancy; risk factors include exposure to oestrogens and high body mass index. Many of the established risk factors for developing endometrial cancer are associated with excess exposure to oestrogen unopposed by progesterone. A high body mass index (BMI) [4,5] increases the risk of developing endometrial cancer and patients with a high BMI have a poorer prognosis [6]. Expression of enzymes involved in biosynthesis of oestrogens such as CYP19A1 and 17β HSD type 2 have been documented in endometrial carcinomas [7,8] and concentrations of oestradiol (E2) in tumour tissues have been correlated positively with the clinical stage of disease and rate of tumour invasion in both pre- and post-menopausal women [9]

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Conclusion