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NOTCH1 activation compensates BRCA1 deficiency and promotes triple-negative breast cancer formation

Author

Listed:
  • Kai Miao

    (University of Macau
    University of Macau)

  • Josh Haipeng Lei

    (University of Macau
    University of Macau)

  • Monica Vishnu Valecha

    (University of Macau
    University of Macau)

  • Aiping Zhang

    (University of Macau
    University of Macau)

  • Jun Xu

    (University of Macau
    University of Macau)

  • Lijian Wang

    (University of Macau
    University of Macau)

  • Xueying Lyu

    (University of Macau
    University of Macau)

  • Si Chen

    (University of Macau
    University of Macau)

  • Zhengqiang Miao

    (University of Macau
    University of Macau)

  • Xin Zhang

    (University of Macau
    University of Macau)

  • Sek Man Su

    (University of Macau
    University of Macau)

  • Fangyuan Shao

    (University of Macau
    University of Macau)

  • Barani Kumar Rajendran

    (University of Macau
    University of Macau)

  • Jiaolin Bao

    (University of Macau
    University of Macau)

  • Jianming Zeng

    (University of Macau
    University of Macau)

  • Heng Sun

    (University of Macau
    University of Macau)

  • Ping Chen

    (University of Macau
    University of Macau)

  • Kaeling Tan

    (University of Macau
    University of Macau)

  • Qiang Chen

    (University of Macau
    University of Macau)

  • Koon Ho Wong

    (University of Macau
    University of Macau)

  • Xiaoling Xu

    (University of Macau
    University of Macau
    University of Macau)

  • Chu-Xia Deng

    (University of Macau
    University of Macau)

Abstract

BRCA1 mutation carriers have a higher risk of developing triple-negative breast cancer (TNBC), which is a refractory disease due to its non-responsiveness to current clinical targeted therapies. Using the Sleeping Beauty transposon system in Brca1-deficient mice, we identified 169 putative cancer drivers, among which Notch1 is a top candidate for accelerating TNBC by promoting the epithelial-mesenchymal transition (EMT) and regulating the cell cycle. Activation of NOTCH1 suppresses mitotic catastrophe caused by BRCA1 deficiency by restoring S/G2 and G2/M cell cycle checkpoints, which may through activation of ATR-CHK1 signalling pathway. Consistently, analysis of human breast cancer tissue demonstrates NOTCH1 is highly expressed in TNBCs, and the activated form of NOTCH1 correlates positively with increased phosphorylation of ATR. Additionally, we demonstrate that inhibition of the NOTCH1-ATR-CHK1 cascade together with cisplatin synergistically kills TNBC by targeting the cell cycle checkpoint, DNA damage and EMT, providing a potent clinical option for this fatal disease.

Suggested Citation

  • Kai Miao & Josh Haipeng Lei & Monica Vishnu Valecha & Aiping Zhang & Jun Xu & Lijian Wang & Xueying Lyu & Si Chen & Zhengqiang Miao & Xin Zhang & Sek Man Su & Fangyuan Shao & Barani Kumar Rajendran & , 2020. "NOTCH1 activation compensates BRCA1 deficiency and promotes triple-negative breast cancer formation," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16936-9
    DOI: 10.1038/s41467-020-16936-9
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    Cited by:

    1. Jianjie Li & Xiaodong Shu & Jun Xu & Sek Man Su & Un In Chan & Lihua Mo & Jianlin Liu & Xin Zhang & Ragini Adhav & Qiang Chen & Yuqing Wang & Tingting An & Xu Zhang & Xueying Lyu & Xiaoling Li & Josh , 2022. "S100A9-CXCL12 activation in BRCA1-mutant breast cancer promotes an immunosuppressive microenvironment associated with resistance to immunotherapy," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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