Missense mutations of GPER1 in breast invasive carcinoma: Exploring gene expression, signal transduction and immune cell infiltration with insights from cellular pharmacology.

G protein-coupled estrogen receptor 1 (GPER1) plays a crucial role in the progression of breast cancer and has emerged as a promising therapeutic target. However, while missense mutations in GPER1 have been detected in breast invasive carcinoma (BIC) samples, the resulting molecular, cellular and pharmacological changes remain unclear. The present study categorized BIC samples from The Cancer Genome Atlas database based on mutation information available in the cBioPortal database. Subsequently, survival analysis was conducted and the samples screened for differentially expressed genes (DEGs). Using these DEGs, the present study performed Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, protein-protein interaction network analysis and hub gene selection. After assessing the prognostic value of hub genes, the immune cell infiltration between mutant and wild-type (WT) groups was analyzed. Finally, a luciferase reporter system was used to assess the cyclic AMP (cAMP) production mediated by GPER1 following treatment with the agonist G-1 for each mutation. The results revealed a significant decrease in progression-free survival and disease-specific survival in the GPER1 mutant group compared with the WT group. Gene expression analysis identified 60 DEGs, all of which were upregulated and significantly enriched in GO terms related to tumor progression, such as organic anion transport, glycosaminoglycan binding and monoatomic ion-gated channel activity. DEGs were also significantly enriched in the PI3K-Akt signaling pathway in KEGG. Hub gene selection and prognostic evaluation identified three genes significantly associated with survival: IL33, STAB2 and CFTR. Immune cell infiltration analysis revealed a significant decrease in CD8 T cell content in the GPER1 mutant group compared with the WT group. Luciferase reporter assays demonstrated that four missense mutations in GPER1 (L129M, E218Q, S235F and A345G) significantly attenuated the induction of cyclic adenosine monophosphate production mediated by its agonist. These findings provided valuable insights for the design of breast cancer drugs targeting GPER1 and for precision medicine initiatives.