title: COPS5 amplification and overexpression confers tamoxifen-resistance in ERα-positive breast cancer by degradation of NCoR.
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.
authors.affiliation: Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University; Department of Oncology, Shanghai Medical School, Fudan University, Shanghai 200032, China.
authors.forename: Renquan
authors.initials: R
authors.lastname: Lu
authors.affiliation: Department of Laboratory Medicine, Long Hua Hospital, Shanghai University of TCM, Shanghai 200032, China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Hu
authors.affiliation: Gerchi Biotech Research Laboratories, 100 Research Park, Zhejiang 314300, China.
authors.forename: Junmei
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University; Department of Oncology, Shanghai Medical School, Fudan University, Shanghai 200032, China.
authors.forename: Jiajun
authors.initials: J
authors.lastname: Sun
authors.affiliation: Gerchi Biotech Research Laboratories, 100 Research Park, Zhejiang 314300, China.
authors.forename: Alan Z
authors.initials: AZ
authors.lastname: Zhu
authors.affiliation: Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University; Department of Oncology, Shanghai Medical School, Fudan University, Shanghai 200032, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University; Department of Oncology, Shanghai Medical School, Fudan University, Shanghai 200032, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University; Department of Oncology, Shanghai Medical School, Fudan University, Shanghai 200032, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang 310016, China.
authors.forename: Xian
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang 310016, China.
authors.forename: Hongchuan
authors.initials: H
authors.lastname: Jin
authors.affiliation: Gerchi Biotech Research Laboratories, 100 Research Park, Zhejiang 314300, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhu
authors.affiliation: Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University; Department of Oncology, Shanghai Medical School, Fudan University, Shanghai 200032, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Guo
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D000075686:COP9 Signalosome Complex / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D061986:MCF-7 Cells; D056971:Nuclear Receptor Co-Repressor 1 / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects*; D013629:Tamoxifen / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; D047908:Intracellular Signaling Peptides and Proteins; C539127:NCOR1 protein, human; D056971:Nuclear Receptor Co-Repressor 1; D025801:Ubiquitin; D013629:Tamoxifen; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex; D046988:Proteasome Endopeptidase Complex