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

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 (ER alpha and ER beta) encoded by separate genes. The full-length receptors function as ligand-activated transcription factors; splice variant isoforms of ER beta 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 PGF2 alpha on expression of ERs and PR. Results: Full length ER beta (ER beta 1) and two ER beta variants (ER beta 2, ER beta 5) 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 ER alpha(neg/low). Expression of PR in endometrial adenocarcinoma (Ishikawa) cell lines and tissues broadly paralleled that of ER alpha. Treatment of adenocarcinoma cells with PGF2 alpha reduced expression of ER alpha but had no impact on ER beta 1. Cells incubated with PGF2 alpha were unable to increase expression of PR mRNA when they were incubated with E2. Conclusion: We have demonstrated that ER beta 5 protein is expressed in stage 1 endometrial adenocarcinomas. Expression of three ER beta variants, including the full-length protein is not grade-dependent and most cells in poorly differentiated cancers are ER beta(pos)/ER alpha(neg). We found evidence of a link between COX-2, its product PGF2 alpha, and expression of ER alpha and PR that sheds new light on the cross talk between steroid and PG signalling pathways in this disease.