GPER and Testicular Germ Cell Cancer

The G protein-coupled estrogen receptor (GPER), also known as GPR30, is a widely conserved 7-transmembrane-domain protein which has been identified as a novel 17 beta-estradiol-binding protein that is structurally distinct from the classic oestrogen receptors (ER alpha and ER beta). There are still conflicting data regarding the exact role and the natural ligand of GPER/GPR30 in reproductive tracts as both male and female knock-out mice are fertile and have no abnormalities of reproductive organs. Testicular germ cell cancers (TGCCs) are the most common malignancy in young males and the most frequent cause of death from solid tumors in this age group. Clinical and experimental studies suggested that estrogens participate in the physiological and pathological control of male germ cell proliferation. In human seminoma cell line, while 17 beta-estradiol (E2) inhibits in vitro cell proliferation through an ER beta-dependent mechanism, an impermeable E2 conjugate (E2 coupled to BSA), in vitro cell proliferation is stimulated by activating ERK1/2 and protein kinase A through a membrane GPCR that we further identified as GPER/GPR30. The same effect was observed with low but environmentally relevant doses of BPA, an estrogenic endocrine disrupting compound. Furthermore, GPER/GPR30 is specifically overexpressed in seminomas but not in non-seminomas and this overexpression is correlated with an ER beta-downregulation. This GPER/GPR30 overexpression could be linked to some genetic variations, as single nucleotide polymorphisms, which was also reported in other hormone-dependent cancers. We will review here the implication of GPER/GPR30 in TGCCs pathophysiology and the arguments to consider GPER/GPR30 as a potential therapeutic target in humans.