Glucocorticoid receptor regulates the epithelial-mesenchymal transition process through GR/ZEB1/E-cad and is involved in breast cancer endocrine drug resistance—a bioinformatics analysis

Abstract

Background Studies have shown that there is a connection between estrogen receptor (ER) and glucocorticoid receptor (GR), which can impact the epithelial-mesenchymal transition (EMT) process and contribute to endocrine resistance in breast cancer. However, the specific mechanism is unclear. It is crucial to investigate this mechanism further. Methods This study aimed to confirm the role of GR in breast cancer endocrine resistance. Based on our hypothesis, GR is linked to a gene involved in the EMT process, and thus contributes to endocrine resistance in breast cancer. We obtained survival data and GR expression data from Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). Additionally, we gathered GR expression data from Gene Expression Omnibus (GEO). Using Cytoscape, we constructed a protein-protein interaction (PPI) network and identified key genes. Data of Vimentin, E-cad, and Wnt/β-catenin expression were obtained from The Cancer Genome Atlas (TCGA). We used the co-expression method to identify key proteins. UALCAN and cBioPortal were utilized to verify the function of the key protein. Results In ER+ breast cancer, GR (P=3.12780899271121E−08) and zinc finger E-box binding homeobox 1 (ZEB1) (P=1.716157E−01) were lowly expressed and down-regulated genes of GR differentially expressed genes were enriched in cell adhesion molecules. We screened for the key protein ZEB1 and found high levels of it was positively associated with prolonged recurrence-free survival (RFS) in patients receiving endocrine therapy (P=0.0024), while high levels of E-cad were negatively associated (P=0.0038). GR expression was positively associated with ZEB1 (Spearman =0.29, P=8.50e−21), negatively associated with E-cad (Spearman =−0.13, P=5.17e−5), and negatively associated with the SETD1B (Spearman =−0.14, P=1.527e−5), a gene downstream of ZEB1. In contrast, ZEB1 expression was negatively correlated with E-cad (Spearman =−0.081, P=3.132e−3) and negatively correlated with SET domain-containing 1B (SETD1B) (Spearman =−0.177, P=9.07e−11). Conclusions In ER+ breast cancers, GR expression is suppressed, and the EMT process is inhibited by suppressing ZEB1 expression and thus promoting E-cad expression. For the investigation of endocrine medication resistance in breast cancer, it is crucial to identify the mechanisms by how GR participates in the EMT process.

Dexamethasone–tamoxifen combination exerts synergistic therapeutic effects in tamoxifen-resistance breast cancer cells

“…While in ER − BC patients, the activation of GR is linked to the expression of genes associated with tumor survival and resistance to chemotherapy. These genes are involved in pathways that inhibit apoptosis and promote epithelial-ṇmesenchymal transition [ 33 , 34 ].…”