Endocrine Abstracts

Endometrial cancer is the most common gynaeological malignancy in the developed world: lifetime exposure to oestrogen is a key risk factor. Oestrogen action is mediated by ligand activated receptors encoded by the ESR1 (ERα) and ESR2 (ERß) genes: ERα plays a key role in regulating endometrial cell proliferation. ERß5, is a truncated variant isoform of ERß formed by alternative splicing of ESR2 that contains a DNA binding domain but lacks the ability to bind E2. ERß5 is expressed in endometrial cancer tissue but its functional impact is unknown. Double fluorescent immunostaining for ERα and ERß5 was performed on sections of endometrial adenocarcinomas recovered from post-menopausal women (n=271) undergoing total abdominal hysterectomy. Reproductive cell lines where infected with lentivirus expressing an ERß5 construct to generate cells with altered ratios of ERß5/ERα to examine the functional impact in an ERE reporter assay. A lentivirus YFP-ERß5 construct was used to investigate intra-nuclear mobility (FRAP) in the cell lines. Fluorescent immunohistochemistry detected cells co-expressing ERß5 and ERα in stage I cancers. Co-expression of ERß5 in an ERα^pos endometrial cancer cell line (Ishikawa) increased ligand-dependent activation of an ERE-luciferase reporter by the ERα-selective ligand PPT. FRAP analysis of YFP-ERß5 in Ishikawa cells revealed incubation with E2 resulted in a transient reduction in intra-nuclear mobility. In ERα^neg MDA breast cancer cells, there was no E2-dependent change in mobility of YFP-ERß5 or activation of the reporter gene. Our results show ERß5 can act as heterodimeric partner to ERα in cells of endometrial stage 1 cancers that may increase their sensitivity to E2. These data suggest immunostaining for ERß5 should be considered in risk assessment of women with stage I endometrial cancers as they could benefit from treatment with drugs that block receptor dimerisation.