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 (ERalpha and ERbeta) encoded by separate genes. The full-length receptors function as ligand-activated transcription factors; splice variant isoforms of ERbeta 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 >or= 10 each group) using qRTPCR, single and double immunohistochemistry. We used endometrial adenocarcinoma cell lines to investigate the impact of PGF2alpha on expression of ERs and PR.
Results: Full length ERbeta (ERbeta1) and two ERbeta variants (ERbeta2, ERbeta5) 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 ERalphaneg/low. Expression of PR in endometrial adenocarcinoma (Ishikawa) cell lines and tissues broadly paralleled that of ERalpha. Treatment of adenocarcinoma cells with PGF2alpha reduced expression of ERalpha but had no impact on ERbeta1. Cells incubated with PGF2alpha were unable to increase expression of PR mRNA when they were incubated with E2.
Conclusion: We have demonstrated that ERbeta5 protein is expressed in stage 1 endometrial adenocarcinomas. Expression of three ERbeta variants, including the full-length protein is not grade-dependent and most cells in poorly differentiated cancers are ERbetapos/ERalphaneg. We found evidence of a link between COX-2, its product PGF2alpha, and expression of ERalpha and PR that sheds new light on the cross talk between steroid and PG signalling pathways in this disease.