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: Renquan Lu, Xiaobo Hu, Junmei Zhou, Jiajun Sun, Alan Z Zhu, Xiaofeng Xu, Hui Zheng, Xiang Gao, Xian Wang, Hongchuan Jin, Ping Zhu, Lin Guo
• Journal: Nature communications (Nat Commun) Vol. 7 Pg. 12044 (07 04 2016) ISSN: 2041-1723 [Electronic] England
• PMID: 27375289 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Estrogen Receptor alpha
• Intracellular Signaling Peptides and Proteins
• NCOR1 protein, human
• Nuclear Receptor Co-Repressor 1
• Ubiquitin
• Tamoxifen
• Peptide Hydrolases
• COPS5 protein, human
• COP9 Signalosome Complex
• Proteasome Endopeptidase Complex

Topics

• Breast Neoplasms (metabolism, pathology)
• COP9 Signalosome Complex (metabolism)
• Down-Regulation (drug effects, genetics)
• Drug Resistance, Neoplasm (drug effects)
• Estrogen Receptor alpha (metabolism)
• Female
• Gene Amplification
• Gene Expression Regulation, Neoplastic (drug effects)
• HEK293 Cells
• Humans
• Intracellular Signaling Peptides and Proteins (metabolism)
• MCF-7 Cells
• Nuclear Receptor Co-Repressor 1 (metabolism)
• Peptide Hydrolases (metabolism)
• Promoter Regions, Genetic (genetics)
• Proteasome Endopeptidase Complex (metabolism)
• Proteolysis (drug effects)
• Tamoxifen (pharmacology)
• Ubiquitin (metabolism)