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Nat Commun. 2016 Jul 4;7:12044. doi: 10.1038/ncomms12044.

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

Author information

1
Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University; Department of Oncology, Shanghai Medical School, Fudan University, Shanghai 200032, China.
2
Department of Laboratory Medicine, Long Hua Hospital, Shanghai University of TCM, Shanghai 200032, China.
3
Gerchi Biotech Research Laboratories, 100 Research Park, Zhejiang 314300, China.
4
Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang 310016, China.

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.

PMID:
27375289
PMCID:
PMC4932188
DOI:
10.1038/ncomms12044
[Indexed for MEDLINE]
Free PMC Article

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