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

• Published in: OncoTargets and therapy Vol. 13; pp. 8887 - 8899
• Main Authors: Ye, Shuang, Xu, Yuanyuan, Wang, Ling, Zhou, Kewen, He, Jiehua, Lu, Jiabin, Huang, Qitao, Sun, Peng, Wang, Tinghuai
• Format: Journal Article
• Language: English
• Published: New Zealand Taylor & Francis Ltd 01-01-2020; Dove
• Subjects: Antibodies; Biotechnology; Breast cancer; Cell adhesion & migration; Cell migration; Cell viability; Gene amplification; Kinases; Ligands; MAP kinase; Medical prognosis; Metabolism; Metastases; Metastasis; Original Research; Prognosis; Proteins; Wound healing; United Kingdom > UK; United States > US; China; Japan; Germany; estrogen; triple-negative breast cancer; ERRα; prognosis; GPER
• ISSN: 1178-6930; 1178-6930
• DOI: 10.2147/OTT.S265372

The present study aims to demonstrate the correlation between estrogen-related receptor α (ERRα) and G protein-coupled estrogen receptor (GPER) expression and its predictive role in the prognosis of patients with triple-negative breast cancer (TNBC).
A retrospective review of 199 cases of TNBC was conducted to assess the GPER and ERRα expression, and its clinicopathologic and prognostic implications. Subsequently, the effects of ERRα and GPER on cell viability, migration, and invasion induced by estrogen were also investigated in vitro.
Compared to TNBCs with ERRα low expression, ERRα-high patients exhibited higher nuclear grade, more frequent lymph nodal metastasis, a higher rate of local recurrence, and distant metastasis. Survival analyses revealed that ERRα-high patients had decreased overall survival (OS), local recurrence-free survival (LRFS), and distant disease-free survival (DDFS) than ERRα-low patients. The GPER expression level positively correlated with ERRα (R=0.167, P=0.18), and TNBCs with ERRα-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 ERRα. Moreover, the overexpression of ERRα 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.
Our findings suggest that ERRα and GPER synergistically predict unfavorable prognosis in TNBCs. Mechanically, GPER mediates the upregulation expression of ERRα induced by estrogen and promotes cell viability, migration, and invasion.