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

Abstract

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). Methods: 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. Results: 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 diseasefree 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. Conclusion: 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.

Current progress and prospects for G protein-coupled estrogen receptor in triple-negative breast cancer

“…An in vitro study suggested that GPER-mediated estrogen-induced ERRα upregulation may promote TNBC cell viability, migration, and invasion. ERRα-GPER interactions lead to a malignant phenotype of TNBC, and this result was consistent with the conclusion drawn from the survival analysis ( Ye et al, 2020 ). Additional research is necessary to determine the potential mechanisms that contribute to the interplay between GPER and ERRα in TNBC.…”

High GPER expression in triple-negative breast cancer is linked to pro-metastatic pathways and predicts poor patient outcomes

“…Ligands including E2 and bisphenol A were claimed to trigger GPER to promote migration and metastasis of TNBC cells [21][22][23] . E2 also induced the up-regulation of estrogenrelated receptor α expression via GPER activation, enhanced the migration and invasion of TNBC cells 55 . Increased GPER expression was observed at the invasive margin in some nests, implying that GPER activation may contribute to the invasion of cancer cells.…”

“…High GPER expression was also related to decreased outcomes, including the local RFS, DDFS, OS, and PFS in a Chinese cohort ( n = 249) 17 . In a retrospective TNBC study ( n = 199), GPER and estrogen-related receptor α (ERR-α) synergistically predicted poor patient outcomes 55 . In summary, studies seem to agree that GPER can mediate estrogen carcinogenesis and promote the progression of TNBC.…”

Immunolocalization of Cytoplasmic ER in ER-negative Breast Carcinoma as a Potent Favorable Prognostic Predictor

“…Our present study demonstrated that cytoplasmic ER was inversely associated to Ki67 LI in the ER-negative breast carcinoma. It is well recognized that ER signaling activation is lack in TNBC [ 29 ]. However, recently Contreras-Zarate et al found that estradiol induced BDNF/TrkB signaling in TNBC to promote brain metastases [ 4 ], and Girgert et al suggested that estradiol significantly increased cell proliferation of TNBC in vitro , along with the activation of Src, EGFR (epidermal growth factor receptor), Cyclin D1, and CREB (cAMP-responsive element binding) signaling [ 8 ].…”