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

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, Jiaolin Bao, Jianming Zeng, Heng Sun, Ping Chen, Kaeling Tan, Qiang Chen, Koon Ho Wong, Xiaoling Xu and Chu-Xia Deng ()
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Kai Miao: University of Macau
Josh Haipeng Lei: University of Macau
Monica Vishnu Valecha: University of Macau
Aiping Zhang: University of Macau
Jun Xu: University of Macau
Lijian Wang: University of Macau
Xueying Lyu: University of Macau
Si Chen: University of Macau
Zhengqiang Miao: University of Macau
Xin Zhang: University of Macau
Sek Man Su: University of Macau
Fangyuan Shao: University of Macau
Barani Kumar Rajendran: University of Macau
Jiaolin Bao: University of Macau
Jianming Zeng: University of Macau
Heng Sun: University of Macau
Ping Chen: University of Macau
Kaeling Tan: University of Macau
Qiang Chen: University of Macau
Koon Ho Wong: University of Macau
Xiaoling Xu: University of Macau
Chu-Xia Deng: University of Macau

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16936-9

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