Comprehensive understanding of the role of GPER in estrogen receptor-alpha negative breast cancer

G protein-coupled estrogen receptor (GPER) plays a prominent role in facilitating the rapid, non-genomic signaling of estrogens in breast cancer cells. Herein, a comprehensive overview of the role of GPER in ER-ɑ-negative breast cancer is provided. Activation of GPER affected proliferation, metastasis and epithelial mesenchymal transition in ER-ɑ negative breast cancer cells. Clinical studies have demonstrated that GPER positivity was strongly correlated with larger tumor size and advanced clinical stage, suggesting that GPER/ERK signaling may play a role in promoting tumor progression. Strong evidence existed that environmental contaminants like bisphenol A have a carcinogenic potential mediated by GPER activation. The complexity of the cross talk between GPER and other receptors including ER-β, ER-α36, Estrogen-related receptor α (ERRα) and androgen receptor has been discussed. The potential utility of small molecules and phytoestrogens targeting GPER, adds valuable insights into its therapeutic potential. This review holds promises in advancing our understanding of GPER role in ER-ɑ-negative breast cancer. Overall, the consequences of GPER activation are still an area of active research and the implication are not entirely clear. •Activation of GPER affected proliferation, metastasis and stemness.•Contaminants like bisphenol A have a carcinogenic potential mediated by GPER activation.•GPER positivity was strongly correlated with larger tumor size and advanced clinical stage.•There is a cross talk between GPER and ER-β, ER-α36, ERR α and androgen receptors.•Small molecules and phytoestrogens targeting GPER may have therapeutic potential.