Open Access Highly Accessed Research article

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 Collins1, Sheila MacPherson1, Pamela Brown1, Vincent Bombail1, Alistair RW Williams3, Richard A Anderson2, Henry N Jabbour1 and Philippa TK Saunders1*

Author Affiliations

1 MRC Human Reproductive Sciences Unit, The University of Edinburgh Centre for Reproductive Biology, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK

2 Division of Reproductive and Developmental Sciences, The University of Edinburgh Centre for Reproductive Biology, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK

3 Division of Pathology, The University of Edinburgh, Simpson Centre for Reproductive Health, 51 Little France Crescent, Edinburgh EH16 4SA, UK

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BMC Cancer 2009, 9:330  doi:10.1186/1471-2407-9-330

Published: 16 September 2009

Abstract

Background

Endometrial 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.

Methods

We 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.

Results

Full 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.

Conclusion

We 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.