Estrogen-Related Receptor α (ERRα) and G Protein-Coupled Estrogen Receptor (GPER) Synergistically Indicate Poor Prognosis in Patients with Triple-Negative Breast Cancer

Purpose: The present study aims to demonstrate the correlation between estrogen-related receptor alpha (ERR alpha) and G protein-coupled estrogen receptor (GPER) expression and its predictive role in the prognosis of patients with triple-negative breast cancer (TNBC). Methods: A retrospective review of 199 cases of TNBC was conducted to assess the GPER and ERR alpha expression, and its clinicopathologic and prognostic implications. Subsequently, the effects of ERR alpha and GPER on cell viability, migration, and invasion induced by estrogen were also investigated in vitro. Results: Compared to TNBCs with ERR alpha low expression, ERR alpha-high patients exhibited higher nuclear grade, more frequent lymph nodal metastasis, a higher rate of local recurrence, and distant metastasis. Survival analyses revealed that ERR alpha-high patients had decreased overall survival (OS), local recurrence-free survival (LRFS), and distant disease free survival (DDFS) than ERR alpha-low patients. The GPER expression level positively correlated with ERR alpha (R=0.167, P=0.18), and TNBCs with ERR alpha-low/GPER-low demonstrated the best survival outcomes among groups. In vitro, E2 significantly enhanced cell viability, migration, and invasion in BT-549 and MDA-MB-231 cell lines, which was associated with the increased expression of ERR alpha. Moreover, the overexpression of ERR alpha induced by estrogen and G1 (GPER agonist) was reversed by knocking down of GPER and blocking the MAPK signaling with PD98059 in both cell lines. Conclusion: Our findings suggest that ERR alpha and GPER synergistically predict unfavorable prognosis in TNBCs. Mechanically, GPER mediates the upregulation expression of ERR alpha induced by estrogen and promotes cell viability, migration, and invasion.