期刊
NATURE COMMUNICATIONS
卷 7, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms12044
关键词
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资金
- Science and Technology Commission of Shanghai Municipality [124119a0202]
- Shanghai Hospital Development Center [SHDC22014002]
- Shanghai Pujiang Talent Plan Sponsorship [14PJD010]
- National Natural Science Foundation of China [NSF-81572552, 81371178]
- Jiaxin municipal government
Oestrogen receptor alpha (ER alpha) antagonists are used in endocrine therapies for ER alpha-positive (ER alpha+) 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 ER alpha+ 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 ER alpha and tamoxifen-mediated suppression of ER alpha 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.
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