Glucocorticoid receptor–IRS-1 axis controls EMT and the metastasis of breast cancers  

作　　者：Weiwei Shi Dongmei Wang Xinwang Yuan Yi Liu Xiaojie Guo Jingsong Li Jianguo Song 

机构地区：[1]State Key Laboratory of Cell Biology,CAS Center for Excellence in Molecular Cell Science,Shanghai Institute of Biochemistry and Cell Biology,Chinese Academy of Sciences,University of Chinese Academy of Sciences,Shanghai 200031,China

出　　处：《Journal of Molecular Cell Biology》2019年第12期1042-1055,共14页分子细胞生物学报（英文版）

基　　金：the Natural Science Foundation of China(81472603 and 81672879).

摘　　要：Glucocorticoid receptor (GR) is involved in the transcriptional regulation of genes that are important for various biological functions, including tumor growth and metastatic progression. However, the cellular and biological effects of GR remain poorly understood. Here, we investigated the role of GR and its underlying mechanism in mediating breast cancer cell survival and metastasis. We observed that the GR levels were increased in drug-resistant breast cancer cells and in metastatic breast cancer samples. GR promoted tumor cell invasion and lung metastasis in vivo. The GR expression levels were negatively correlated with the survival rates of breast cancer patients. Both ectopic expression and knockdown of GR revealed that GR is a strong inducer of epithelial-to-mesenchymal transition (EMT), which is consistent with its effects on cell survival and metastasis. GR suppressed the expression of insulin receptor substrate 1 (IRS-1) by acting as an IRS-1 transcriptional repressor. In addition, GR has an opposite effect on the expression levels of IRS-2, indicating that GR is able to differentially regulate the IRS-1 and IRS-2 expression. The cellular and biological effects elicited by GR were consistent with the reduced levels of IRS-1 observed in cancer cells, and GR-mediated IRS-1 suppression activated the ERK2 MAP kinase pathway, which is required for GR-mediated EMT. Taken together, our results indicate that GR–IRS-1 signaling axis plays an essential role in regulating the survival, invasion, and metastasis of breast cancer cells.

关 键 词：METASTASIS BREAST INVASION 

分 类 号：R73[医药卫生—肿瘤]