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.
Highlights
Breast cancer (BC) is the most frequently diagnosed tumor worldwide (24.2%) and the leading cause of cancer death among females (14.5%) [1]
We recently found that G protein-coupled estrogenreceptor receptor (GPER) mediates the activation of the focal adhesion kinase (FAK) and the formation of focal adhesions (FAs) in triple negative BC cells (TNBC), contributing to the acquisition of aggressive features by breast malignancies [9]
Our analysis provides new insights regarding the association of pro-metastatic pathways with GPER in the estrogen receptor (ER)-negative BC, opening a new scenario for subsequent studies aimed to better evaluate its role in breast tumors characterized by a worse prognosis
Summary
Breast cancer (BC) is the most frequently diagnosed tumor worldwide (24.2%) and the leading cause of cancer death among females (14.5%) [1]. The activation of GPER triggers diverse transduction pathways including the epidermal growth factor receptor (EGFR), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), and mitogen-activated protein kinases (MAPKs) toward transcriptional and biological responses driving the progression of BC [5,6,7,8]. In this regard, we recently found that GPER mediates the activation of the focal adhesion kinase (FAK) and the formation of focal adhesions (FAs) in triple negative BC cells (TNBC), contributing to the acquisition of aggressive features by breast malignancies [9]. These controversial observations may deserve further investigations in order to better assess prognostic and therapeutic values of GPER, in BC
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