HRD1 sensitizes breast cancer cells to Tamoxifen by promoting S100A8 degradation
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YanYang Wang1,*, AiBin Guo2,*, XiuBin Liang3, Min Li3, Ming Shi1, Yan Li4, Gareth Jenkins5, XiaWen Lin1, XueFei Wei1, ZhiJun Jia1, XueFeng Feng1, DongMing Su4, WanHua Guo1
1Department of Nuclear Medicine, The Affiliated Drum Tower Hospital of Nanjing University, Nanjing, China
2Department of Geriatric Medicine, The Affiliated Drum Tower Hospital of Nanjing University, Nanjing, China
3Department of Surgical Oncology, The First Affiliated Hospital With Nanjing Medical University, Nanjing, China
4Center of Pathology and Clinical Laboratory, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
5Institute of Advanced Materials, Nanjing University of Post and Telecommunication, Nanjing, China
*These authors contributed equally to this work
DongMing Su, email: [email protected]
WanHua Guo, email: [email protected]
Keywords: Tamoxifen, HRD1, S100A8, chemotherapy resistance
Received: July 20, 2016 Accepted: February 06, 2017 Published: March 01, 2017
Estrogen receptor alpha positive (ER+) of breast cancer could develop resistance to antiestrogens including Tamoxifen. Our previous study showed that the E3 ubiquitin ligase HRD1 played an important role in anti-breast cancer. However, its role in chemotherapy resistance hasn’t been reported. In this study, we found that HRD1 expression was downregulated in Tamoxifen-resistant breast cancer cell line MCF7/Tam compared to the Tamoxifen sensitive cell line MCF7. Moreover, S100A8 is the direct target of HRD1 by proteome analysis. Our data showed that HRD1 decreased the protein level of S100A8 through ubiquitination while HRD1 was regulated by acetylation of histone. More importantly, HRD1 knockdown significantly increased the cell survival of MCF7 cells to the Tamoxifen treatment. HRD1 overexpression sensitized MCF7/Tam cells to the Tamoxifen treatment in vitro and in vivo. In conclusion, the decrease of HRD1 expression contributed to Tamoxifen resistance in breast cancer.
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