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

Abstract

Triple-negative breast cancer (TNBC) is a particularly aggressive and heterogeneous disease with few effective targeted therapies and precision therapeutic options over a long period. It is generally considered that TNBC is an estrogen-independent breast cancer, while a new estrogen receptor, namely G protein-coupled estrogen receptor (GPER), is demonstrated to mediate estrogenic actions in TNBC. Based on our transcriptomic analysis, expression of GPER was correlated with clinicopathological variables and survival of 360 TNBC patients. GPER expression at mRNA level was significantly correlated with immunohistochemistry scoring in 12 randomly chosen samples. According to the cutoff value, 26.4% (95/360) of patients showed high GPER expression and significant correlation with the mRNA subtype of TNBC (P = 0.001), total metastatic events (P = 0.019) and liver metastasis (P = 0.011). In quantitative comparison, GPER abundance is correlated with the high-risk subtype of TNBC. At a median follow-up interval of 67.1 months, a significant trend towards reduced distant metastasis-free survival (DMFS) (P = 0.014) was found by Kaplan–Meier analysis in patients with high GPER expression. Furthermore, univariate analysis confirmed that GPER was a significant prognostic factor for DMFS in TNBC patients. Besides, high GPER expression was significantly linked to the worse survival in patients with lymph node metastasis, TNM stage III as well as nuclear grade G3 tumors. Transcriptome-based bioinformatics analysis revealed that GPER was linked to pro-metastatic pathways in our cohort. These results may supply new insights into GPER-mediated estrogen carcinogenesis in TNBC, thus providing a potential strategy for endocrine therapy of TNBC.

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

“…In vivo studies revealed that breast cancer in GPER-knockout mice resulted in diminished lung metastases compared with that in wild-type mice, indicating that animals with low or no GPER expression tend to develop less aggressive breast tumors ( Marjon et al, 2014 ). Recent research has shown a significant correlation between GPER abundance and high-risk TNBC, characterized by G3 tumors, distant metastasis, stage III, and lymph node metastasis ( Xu et al, 2022 ). Differing opinions suggest that GPER expression may suppress tumor initiation and progression ( Weißenborn et al, 2014 ).…”

“…Elevated GPER expression is directly related to a poor prognosis in TNBC ( Steiman et al, 2013 ; Xu et al, 2022 ). Specifically, decreasing GPER expression with siRNA has been demonstrated to effectively inhibit the proliferation of TNBC cells ( Girgert et al, 2012 ; 2014 ).…”

A Basic Review on Estrogen Receptor Signaling Pathways in Breast Cancer

“…GPER, a seven transmembrane domain protein, that can trigger rapid cellular effects of estrogen [ 87 ], is also expressed in different organs such as liver and adipose tissue in addition to the mammary gland [ 88 ]. GPER expression has also been reported in several types of breast cancer cells [ 89 ]. Its stimulation by estrogen increases cAMP concentrations and the mobilization of intracellular calcium [ 90 , 91 ].…”

Divergent features of ERβ isoforms in triple negative breast cancer: progress and implications for further research

“…However, Kyriakopoulou et al have reported that ERβ mediating EGFR induces aggressiveness and stemness of TNBC (Kyriakopoulou et al, 2020;Kyriakopoulou et al, 2022). G protein-coupled estrogen receptor 1 (GPER1), a member of G protein-coupled receptors (GPCRs), is activated by estradiol, and GPER1 expression is correlated with increasing aggressiveness of TNBC (Girgert et al, 2019;Xu et al, 2022). In a recent study, the anti-invasive effect of ERβ agonists was increased by GPER suppression (Schmitz et al, 2022); however, ERβ1 did not directly regulate the expression of GPER mRNA.…”