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

ABSTRACT: Oestrogen receptor ? (ER?) antagonists are used in endocrine therapies for ER?-positive (ER?+) 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?+ 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? and tamoxifen-mediated suppression of ER? 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.

SUBMITTER: Lu R 

PROVIDER: S-EPMC4932188 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature