The G Protein-Coupled Estrogen Receptor (GPER) Expression Correlates with Pro-Metastatic Pathways in ER-Negative Breast Cancer: A Bioinformatics Analysis

Abstract

The G protein-coupled estrogen receptor (GPER, formerly known as GPR30) is a seven-transmembrane receptor that mediates estrogen signals in both normal and malignant cells. In particular, GPER has been involved in the activation of diverse signaling pathways toward transcriptional and biological responses that characterize the progression of breast cancer (BC). In this context, a correlation between GPER expression and worse clinical-pathological features of BC has been suggested, although controversial data have also been reported. In order to better assess the biological significance of GPER in the aggressive estrogen receptor (ER)-negative BC, we performed a bioinformatics analysis using the information provided by The Invasive Breast Cancer Cohort of The Cancer Genome Atlas (TCGA) project and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) datasets. Gene expression correlation and the statistical analysis were carried out with R studio base functions and the tidyverse package. Pathway enrichment analysis was evaluated with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway on the Database for Annotation, Visualization and Integrated Discovery (DAVID) website, whereas gene set enrichment analysis (GSEA) was performed with the R package phenoTest. The survival analysis was determined with the R package survivALL. Analyzing the expression data of more than 2500 primary BC, we ascertained that GPER levels are associated with pro-migratory and metastatic genes belonging to cell adhesion molecules (CAMs), extracellular matrix (ECM)-receptor interaction, and focal adhesion (FA) signaling pathways. Thereafter, evaluating the disease-free interval (DFI) in ER-negative BC patients, we found that the subjects expressing high GPER levels exhibited a shorter DFI in respect to those exhibiting low GPER levels. Overall, our results may pave the way to further dissect the network triggered by GPER in the breast malignancies lacking ER toward a better assessment of its prognostic significance and the action elicited in mediating the aggressive features of the aforementioned BC subtype.

Microenvironmental Determinants of Breast Cancer Metastasis: Focus on the Crucial Interplay Between Estrogen and Insulin/Insulin-Like Growth Factor Signaling

“…In this vein, immunohistochemical studies showed that GPER levels are positively associated with tumor size, distant metastases, and recurrence in BC specimens and inversely correlated with disease-free survival in tamoxifentreated patients (Filardo et al, 2006;Liu et al, 2009;Ignatov et al, 2011). A recent bioinformatics analysis in ER-negative BCs has endorsed the aforementioned findings, proving that high GPER levels are both linked with promigratory and metastatic genes and positively correlated with a shorter disease-free interval (Talia et al, 2020). Nevertheless, some studies have reported a tumor suppressor function of GPER (Weißenborn et al, 2014;Martin et al, 2018), warranting further investigations in order to better appreciate the role of GPER in different cancer cell contexts.…”

Binding of Androgen- and Estrogen-Like Flavonoids to Their Cognate (Non)Nuclear Receptors: A Comparison by Computational Prediction

“…As mentioned, the only estrogen membrane receptor known so far is GPER, a seven transmembrane G-protein coupled receptor, which is involved in the modulation of signaling processes that promote tumor growth both in vitro and in vivo [ 33 , 34 , 35 ]. Its expression is correlated to increased tumor size, distant metastasis, tumor recurrence [ 36 , 37 ], and expression of pro-metastatic genes in ER-negative breast tumors [ 38 ]. All of these properties make it a promising therapeutic target for treating different types of tumors [ 39 ].…”

The influence of phytoestrogens on different physiological and pathological processes: An overview

“…It was found that ERβ exerts antagonist effects on ERα mediated stimulation in cell proliferation (Covaleda et al, 2008; Strom et al, 2004; Thomas & Gustafsson, 2011). GPER1 is associated with transcriptional and biological responses driving the progression of breast cancer as pro‐migratory and metastatic genes belonging to cell adhesion molecules, triggers diverse transduction pathways including the epidermal growth factor receptor, phosphatidylinositol 3‐kinase/protein kinase B, and mitogen‐activated protein kinases toward (Talia et al, 2020). In male, higher estrogen levels have been related with better cognitive performance (Kulkarni, Gavrilidis, Worsley, van Rheenen, & Hayes, 2013).…”