COPS5 amplification and overexpression confers tamoxifen-resistance in ERα-positive breast cancer by degradation of NCoR
| العنوان: | COPS5 amplification and overexpression confers tamoxifen-resistance in ERα-positive breast cancer by degradation of NCoR |
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| المؤلفون: | Xiaobo Hu, Jiajun Sun, Alan Z. Zhu, Junmei Zhou, Hongchuan Jin, Xian Wang, Lin Guo, Hui Zheng, Ping Zhu, Renquan Lu, Xiang Gao, Xiaofeng Xu |
| المصدر: | Nature Communications Nature Communications, Vol 7, Iss 1, Pp 1-13 (2016) |
| بيانات النشر: | Springer Science and Business Media LLC, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, Proteasome Endopeptidase Complex, Science, Down-Regulation, General Physics and Astronomy, Breast Neoplasms, Drug resistance, Bioinformatics, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, In vivo, medicine, Humans, Nuclear Receptor Co-Repressor 1, Promoter Regions, Genetic, skin and connective tissue diseases, Regulation of gene expression, Multidisciplinary, COP9 Signalosome Complex, Ubiquitin, business.industry, HEK 293 cells, Estrogen Receptor alpha, Gene Amplification, Intracellular Signaling Peptides and Proteins, General Chemistry, medicine.disease, Gene Expression Regulation, Neoplastic, Isopeptidase activity, Tamoxifen, HEK293 Cells, 030104 developmental biology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Proteolysis, MCF-7 Cells, Cancer research, Female, business, Corepressor, hormones, hormone substitutes, and hormone antagonists, Peptide Hydrolases, medicine.drug |
| الوصف: | 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. The corepressor NCoR is required for tamoxifen-mediated ERα-dependent transcriptional repression. Here, the authors show that COPS5 confers tamoxifen-resistance through the degradation of NCOR, the recruitment of the co-activator PCAF to ERα binding sites and the subsequent ERα transcriptional activity. |
| تدمد: | 2041-1723 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::78550151554b191df072b3158a0fd502Test https://doi.org/10.1038/ncomms12044Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....78550151554b191df072b3158a0fd502 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
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