Glucocorticoid receptor regulates the EMT process through GR/ZEB1/E-cad and is involved in breast cancer endocrine drug resistance

Abstract Background The glucocorticoid receptor (GR), estrogen receptor (ER), progesterone receptor (PR), and androgen receptor (AR) belong to the steroid receptor family. Studies have shown that there is a cross-regulation between ER and GR that can affect the EMT process. Methods The present study verified the promoting effect of GR on breast cancer endocrine resistance. Survival and GR gene expression data was obtained from the METABRIC. GR gene expression profiling data were obtained from the GEO. Cytoscape was used to construct a PPI network and screen the key genes. Vimentin, E-cad, and Wnt/β-catenin gene expression data was obtained from TCGA. The co-expression method was employed to screen the key protein. The UALCAN and cBioPortal were used to verify the function of the key protein. Results In ER + breast cancer, GR and zinc finger E-box binding homeobox 1 (ZEB1) were lowly expressed and KEGG showed that down-regulated genes of GR differentially expressed genes were mainly enriched in cell adhesion molecules. We screened for the key protein ZEB1 and found that high levels of this protein in ER + breast cancer were positively associated with prolonged RFS in patients receiving endocrine therapy, while high levels of E-cad were negatively associated. GR expression was positively associated with ZEB1, negatively associated with E-cad, and negatively associated with the SET domain-containing 1B, histone lysine methyltransferase (SETD1B), a gene downstream of ZEB1. In contrast, ZEB1 expression was negatively correlated with E-cad and negatively correlated with SETD1B. 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.