COPS5 amplification and overexpression confers tamoxifen-resistance in ERα-positive breast cancer by degradation of NCoR

Renquan Lu, Xiaobo Hu, Junmei Zhou, Jiajun Sun, Alan Z. Zhu, Xiaofeng Xu, Hui Zheng, Xiang Gao, Xian Wang, Hongchuan Jin, Ping Zhu () and Lin Guo ()
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Renquan Lu: Shanghai Cancer Center, Shanghai Medical School, Fudan University
Xiaobo Hu: Long Hua Hospital, Shanghai University of TCM
Junmei Zhou: Gerchi Biotech Research Laboratories, 100 Research Park, Zhejiang 314300, China
Jiajun Sun: Shanghai Cancer Center, Shanghai Medical School, Fudan University
Alan Z. Zhu: Gerchi Biotech Research Laboratories, 100 Research Park, Zhejiang 314300, China
Xiaofeng Xu: Shanghai Cancer Center, Shanghai Medical School, Fudan University
Hui Zheng: Shanghai Cancer Center, Shanghai Medical School, Fudan University
Xiang Gao: Shanghai Cancer Center, Shanghai Medical School, Fudan University
Xian Wang: Sir Run Run Shaw Hospital
Hongchuan Jin: Sir Run Run Shaw Hospital
Ping Zhu: Gerchi Biotech Research Laboratories, 100 Research Park, Zhejiang 314300, China
Lin Guo: Shanghai Cancer Center, Shanghai Medical School, Fudan University

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract Oestrogen receptor α (ERα) antagonists are used in endocrine therapies for ERα-positive (ERα+) breast cancer patients. Unfortunately the clinical benefit is limited due to intrinsic and acquired drug resistance. Here using integrated genomic and functional studies, we report that amplification and/or overexpression of COPS5 (CSN5/JAB1) confers resistance to tamoxifen. Amplification and overexpression of COPS5, a catalytic subunit of the COP9 complex, is present in about 9% of the ERα+ primary breast cancer and more frequently (86.7%, 26/30) in tamoxifen-refractory tumours. Overexpression of COPS5, through its isopeptidase activity, leads to ubiquitination and proteasome-mediated degradation of NCoR, a key corepressor for ERα and tamoxifen-mediated suppression of ERα target genes. Importantly, COPS5 overexpression causes tamoxifen-resistance in preclinical breast cancer models in vitro and in vivo. We also demonstrate that genetic inhibition of the isopeptidase activity of COPS5 is sufficient to re-sensitize the resistant breast cancer cells to tamoxifen-treatment, offering a potential therapeutic approach for endocrine-resistant breast cancer patients.

Date: 2016
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DOI: 10.1038/ncomms12044

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