HRD1 suppresses the growth and metastasis of breast cancer cells by promoting IGF-1R degradation

• Published in: Oncotarget 2015-12, Vol.6 (40), p.42854-42867
• Main Authors: Xu, Yue-Mei, Wang, Hong-Jiang, Chen, Fang, Guo, Wan-Hua, Wang, Yan-Yang, Li, Hang-Yu, Tang, Jin-Hai, Ding, Ying, Shen, Ya-Chen, Li, Min, Xuan, Wen-Ying, Liu, Lin-Hui, Wang, Jia, Wang, Xue-Rong, Gao, Ze-Jun, Liang, Xiu-Bin, Su, Dong-Ming
• Format: Article
• Language: English
• Subjects: Aged; Animals; Blotting, Western; Breast Neoplasms - metabolism; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Proliferation - physiology; Chromatin Immunoprecipitation; Down-Regulation; Epithelial-Mesenchymal Transition - physiology; Female; Gene Expression Regulation, Neoplastic - physiology; Heterografts; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Mice; Mice, Nude; Middle Aged; Neoplasm Invasiveness - pathology; Real-Time Polymerase Chain Reaction; Receptor, IGF Type 1 - metabolism; Research Paper; RNA, Small Interfering; Tissue Array Analysis; Transfection; Ubiquitin-Protein Ligases - metabolism
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.5733

HRD1 (3-hydroxy-3-methylglutaryl reductase degradation) is an E3 ubiquitin ligase. We found that HRD1 was significantly downregulated in 170 breast cancer tissues. Low tumoral HRD1 expression was correlated with clinicopathological characteristics and a shorter survival in breast cancer patients. P65 specifically bound to the HRD1 promoter and inhibited HRD1 expression. Suppression of NF-κB activity reversed IL-6-induced downregulation of HRD1 expression. HRD1 interacted with IGF-1R and promoted its ubiquitination and degradation by the proteasome. Overexpression of HRD1 resulted in the inhibition of growth, migration and invasion of breast cancer cells in vitro and in vivo. Furthermore, HRD1 attenuated IL-6-induced epithelial-mesenchymal transition in MCF10A cells. These findings uncover a novel role for HRD1 in breast cancer.