HRD1 suppresses the growth and metastasis of breast cancer cells by promoting IGF-1R degradation
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Yue-Mei Xu1,*, Hong-Jiang Wang2,*, Fang Chen3,*, Wan-Hua Guo4,*, Yan-Yang Wang4,*, Hang-Yu Li5,*, Jin-Hai Tang6,*, Ying Ding1, Ya-Chen Shen7, Min Li1,7, Wen-Ying Xuan1, Lin-Hui Liu1, Jia Wang2, Xue-Rong Wang1, Ze-Jun Gao1, Xiu-Bin Liang7, Dong-Ming Su1,7,8
1State Key Laboratory of Reproductive Medicine, Department of Pathology, Nanjing Medical University, Nanjing, China
2Department of Breast Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, China
3Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China
4Department of Nuclear Medicine, The Affiliated Drum Tower Hospital of Nanjing University, Nanjing, China
5Department of General Surgery, 4th Affiliated Hospital, China Medical University, Shenyang, China
6Department of General Surgery, The Affiliated Jiangsu Cancer Hospital, Nanjing Medical University, Nanjing, China
7Center of Metabolic Research, Nanjing Medical University, Nanjing, China
8Center of Cellular therapy, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
*These authors have contributed equally to this work
Dong-Ming Su, e-mail: [email protected]
Keywords: HRD1, breast cancer, metastasis, IGF-1R, degradation
Received: May 02, 2015 Accepted: October 09, 2015 Published: October 19, 2015
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.
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