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

Author

Listed:
  • Renquan Lu

    (Shanghai Cancer Center, Shanghai Medical School, Fudan University
    Shanghai Medical School, Fudan University)

  • Xiaobo Hu

    (Long Hua Hospital, Shanghai University of TCM)

  • Junmei Zhou

    (Gerchi Biotech Research Laboratories, 100 Research Park, Zhejiang 314300, China)

  • Jiajun Sun

    (Shanghai Cancer Center, Shanghai Medical School, Fudan University
    Shanghai Medical School, Fudan University)

  • Alan Z. Zhu

    (Gerchi Biotech Research Laboratories, 100 Research Park, Zhejiang 314300, China)

  • Xiaofeng Xu

    (Shanghai Cancer Center, Shanghai Medical School, Fudan University
    Shanghai Medical School, Fudan University)

  • Hui Zheng

    (Shanghai Cancer Center, Shanghai Medical School, Fudan University
    Shanghai Medical School, Fudan University)

  • Xiang Gao

    (Shanghai Cancer Center, Shanghai Medical School, Fudan University
    Shanghai Medical School, Fudan University)

  • Xian Wang

    (Sir Run Run Shaw Hospital)

  • Hongchuan Jin

    (Sir Run Run Shaw Hospital)

  • Ping Zhu

    (Gerchi Biotech Research Laboratories, 100 Research Park, Zhejiang 314300, China)

  • Lin Guo

    (Shanghai Cancer Center, Shanghai Medical School, Fudan University
    Shanghai Medical School, Fudan University)

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.

Suggested Citation

  • 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, 2016. "COPS5 amplification and overexpression confers tamoxifen-resistance in ERα-positive breast cancer by degradation of NCoR," Nature Communications, Nature, vol. 7(1), pages 1-13, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12044
    DOI: 10.1038/ncomms12044
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