G protein-coupled estrogen receptor 1 (GPER) in the female reproductive tract: from physiology to cancer

Sammanfattning: Estrogen effects are mediated either through genomic action involving the classical estrogen receptors, estrogen receptor alpha (ERα) and beta (ERß), which function as transcription factors in the nucleus, or through rapid non-genomic action via receptors associated with plasma membrane. Recently, a member of the G protein-coupled receptor family was ascribed estrogen receptor properties and proposed as a candidate for mediating non-genomic estrogen signaling. G protein-coupled estrogen receptor, GPER, has a high affinity for estrogen and signals via various mitogenic pathways. The present studies have analyzed GPER mRNA and protein in estrogen sensitive tissues, such as normal endometrium from different phases of the menstrual cycle, early pregnancy decidua, endometrial hyperplasia, endometrial cancer, and ovarian tumors using real-time reverse transcription-polymerase chain reaction (RT-qPCR), in situ hybridization, Western blot, immunohistochemistry, and immune transmission electron microscopy. Endometrial GPER mRNA, mainly localized in glandular epithelial cells, was higher in the proliferative phase than in the secretory phase and early pregnancy decidua. In contrast, GPER protein had no cyclical variations. Compared to normal proliferative endometrium, atypical hyperplasia and endometrial cancer had reduced levels of GPER mRNA, whereas GPER protein was increased. The pattern of GPER gene expression in normal endometrium, hyperplasia, and cancer resembled that of ERα. GPER protein was detected in the plasma membrane, endoplasmic reticulum, mitochondria, filaments, and cytosolic vesicles of endometrial cells. A shift in the subcellular distribution from the endoplasmic reticulum to the plasma membrane was observed in the pathological endometrial cells. About one-third of malignant ovarian tumors had significant expression of GPER protein, but patient survival was not affected by GPER expression. GPER mRNA expression profile between ovarian tumor groups resembled that of ERα, but not that of ERß. IPO8 and RPL4 were identified as suitable reference genes for the normalization of target gene expression in RT-qPCR studies of ovarian tumors. We have described GPER expression in tissues, which have not been explored previously. GPER seems to be linked to proliferation in some conditions, possibly in collaboration with ERα. We have identified new subcellular localizations of GPER and differences in its distribution between normal and pathological cells, which open up for new insights into GPER function.