Most ovarian cancers are epithelial in origin. Preliminary studies suggest that ERβ levels (protein and mRNA) in epithelial ovarian cancer decline relative to levels in normal ovary.[69–72] Overexpressing ERβ in an ovarian adenocarcinoma cancer cell line PEO14 led to a 50% reduction in proliferative capacity. The prognostic significance of ER expression by ovarian cancers has received little attention, although one study reported a correlation between levels of ERβ expression and cancer disease stage, with levels declining with increased severity of disease. In addition, breast cancer studies indicate that tumors positive for ERβ respond better to endocrine therapy. Thus loss of ERβ expression may be a feature of malignant transformation.
An antitumoral role of ERβ in SK-OV-3 ovarian cancer cells that do not express functional ERα was reported. Reduced proliferation, inhibited motility, and increased apoptosis of SK-OV-3 cells overexpressing ERβ1 were noted. Exon-deleted ERβ1 splice variants ERβ-δ125 and ERβ-δ1256, which lack the AF-1 domain and have deletions in their DNA and LBDs, had no effect on proliferation or apoptosis but partly inhibited motility of these cells. Genes associated with these physiological changes include an increase in p21 (WAF1), a cell cycle inhibitor, downregulation of cyclin A2, an estrogen-responsive cell cycle regulator, and an increase in fibullin-1c, an extracellular matrix protein overexpressed in epithelial ovarian cancers and involved in motility.[76,77] ERβ activity may be reduced as a result of DNA methylation. Studies investigating epithelial ovarian carcinoma revealed that human promoter 0N was significantly methylated in ovarian cancer cell lines and tissues and that this methylation correlated with decreases in the expression of exon 0N, ERβ1, ERβ2, and ERβ4. Furthermore, treatment of ovarian cancer cells in vitro with demethylating agents has been shown to restore ERβ activity and inhibit growth, suggesting that ERβ activity is antitumorigenic.
GCTs account for ~5% of all ovarian cancers. GCT and GCT-derived cell lines abundantly express ERβ, and their molecular phenotype is similar to preovulatory granulosa cells.[80–83] As in other endocrine tumors, ERβ may be of pathogenetic significance. The steroid receptor coactivators SRC-1, -2 and -3 and the co-repressors NcoR and SMRT are also expressed by GCT. Despite ERβ expression and estradiol binding, when GCT cell lines were transfected with estrogen-responsive reporter genes and treated with estradiol, there was no response. The activation state of several signaling pathways in these lines was examined with both nuclear factor (NF)κB and AP-1 signaling found to be constitutively active. When the NFκB activity is inhibited by BAY 11-7082, ligand-dependent steroid receptor-mediated transactivation occurs for both exogenous and endogenous ERβ. Thus ERβ signaling in GCT cell lines is transrepressed via the NFκB pathway.
Few studies have examined NFκB signaling in normal granulosa cells. We have localized p65 (RelA), a member of the NFκB family to granulosa cells, theca cells, oocytes, and luteal cells of adult rat ovary with both cytoplasmic and nuclear staining evident. Wang et al reported that the NFκB pathway mediates the FSH-induced expression of X-linked inhibitor of apoptosis (XIAP) by granulosa cells. These data are consistent with a role for NFκB signaling in granulosa cells and indicate that ERβ signaling may be modulated by NFκB, perhaps through mutual transrepression. In malignant granulosa cells, inhibition of ERβ signaling by NFκB may be enhanced by cyclin D2. Together, these data suggest that in both normal granulosa cell proliferation and in malignancy (GCT), the action of ERβ is inhibited by pro-proliferative signaling pathways, arguing that its role may be primarily to inhibit proliferation and/or promote differentiation. In GCT this may contribute to the pathogenesis by interrupting part of an autocrine loop that contributes to limiting the FSH-like growth stimulation.
Semin Reprod Med. 2012;30(1):32-38. © 2012 Thieme Medical Publishers