Figure 3.

Working hypothesis for a role of E2 signaling in GCT. ERβ is expressed in all GCT [31,136,137]. There is a heterogeneity of ER subtypes expression among GCT [31,136,137,139,140,141,142]. In GCT, all ERβ isoforms are localized in the nucleus [31,33], except for ERβ2, which is also present in the cytosol, possibly interacting with mitochondrial Bcl-2 [33] to promote GCT survival. GCT produce E2 that could bind to GPER1 and promote the inhibition of GCT migration and invasion, in the absence of ERα [135] (A). In addition, E2 could bind to ERβ1, which would either homodimerize or heterodimerize with ERβ5 or ERβ2 [20], in the absence of ERα, to regulate pro-survival or pro-apoptotic gene expression, through DNA interactions with ERE, AP-1, or SP-1 sites [56]. ERβ1, ERβ2, and ERβ5 might also trigger non-genomic pathways that still need to be identified in GCT. (B) In the presence of ERα, E2 binding would induce its homo- or heterodimerization with other ER subtypes that would finally regulate the expression of other sets of pro-survival genes. ERβ isoforms inhibit the transcriptional activity of ERα [22]. In addition, E2 could also bind to ERβ1 or ERα, which are expressed in endothelial cells, to respectively reduce or stimulate angiogenesis [166,167]. The presence of specific ER subtypes probably orientates the fate of GCT.