Identification of G protein-coupled estrogen receptor as an estrogen receptor associated with non-skull base meningiomas.

OBJECTIVE: The authors aimed to systematically investigate the expression and subcellular localization of estrogen receptors ERα and GPER in meningioma and to evaluate the functional impact of estradiol on cell viability in common meningioma cell lines and primary patient-derived cultures. METHODS: Tissue microarrays (TMAs) representing 120 patients (82 female, median age at diagnosis 57 years) with meningiomas (564 regions of interest) were analyzed using quantitative digital image analysis (QuPath) to evaluate nuclear and cytoplasmic receptor density. Subcellular localization was validated via immunofluorescence in meningeal and meningioma cell lines. Functional responsiveness to 17β-estradiol (E2) was assessed using in vitro cell viability assays with common meningioma cell lines Ben-Men-1, CH157-MN, IOMM-Lee, human meningeal cells, and primary cultured dura. RESULTS: GPER was ubiquitously expressed across the cohort, exhibiting both cytoplasmic and nuclear localization, whereas ERα detection was comparatively limited. Multivariable linear regression analysis identified the anatomical location as a significant independent predictor of GPER expression. Non-skull base tumors demonstrated higher GPER staining intensity compared with that of skull base tumors (nuclear, p = 0.013; cytoplasmic, p = 0.011). GPER staining intensity also varied across genomic alteration subgroups, with lower intensity observed in the TRAF7 ± other subgroup compared with NF2/22q-loss tumors. In vitro experiments revealed a biphasic response to E2 in which low-dose exposure (1-10 pM) was frequently associated with reduced viability, whereas higher concentrations (10-100 nM) increased cell viability. These effects varied across cell lines, with the NF2-loss CH157-MN meningioma cell line demonstrating the most pronounced increase in viability at 100 nM (adjusted p = 0.0002). CONCLUSIONS: These findings provide a systematic protein-level characterization of estrogen receptor expression in meningioma, identify GPER as a predominant receptor with expression patterns associated with tumor location and genomic subgroup, and lay the foundation for future mechanistic and translational studies.