HRD1 sensitizes breast cancer cells to Tamoxifen by promoting S100A8 degradation

// YanYang Wang 1, * , AiBin Guo 2, * , XiuBin Liang 3 , Min Li 3 , Ming Shi 1 , Yan Li 4 , Gareth Jenkins 5 , XiaWen Lin 1 , XueFei Wei 1 , ZhiJun Jia 1 , XueFeng Feng 1 , DongMing Su 4 , WanHua Guo 1 1 Department of Nuclear Medicine, The Affiliated Drum Tower Hospital of Nanjing University, Nanjing, China 2 Department of Geriatric Medicine, The Affiliated Drum Tower Hospital of Nanjing University, Nanjing, China 3 Department of Surgical Oncology, The First Affiliated Hospital With Nanjing Medical University, Nanjing, China 4 Center of Pathology and Clinical Laboratory, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China 5 Institute of Advanced Materials, Nanjing University of Post and Telecommunication, Nanjing, China * These authors contributed equally to this work Correspondence to: DongMing Su, email: sudongming@njmu.edu.cn WanHua Guo, email: wanhuaguo@163.com Keywords: Tamoxifen, HRD1, S100A8, chemotherapy resistance Received: July 20, 2016      Accepted: February 06, 2017      Published: March 01, 2017 ABSTRACT 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.