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NOTCH1 activation compensates BRCA1 deficiency and promotes triple-negative breast cancer formation
Miao,Kai1,2; Lei,Josh Haipeng1,2; Valecha,Monica Vishnu1,2; Zhang,Aiping1,2; Xu,Jun1,2; Wang,Lijian1,2; Lyu,Xueying1,2; Chen,Si1,2; Miao,Zhengqiang1,3; Zhang,Xin1,4; Su,Sek Man1,2; Shao,Fangyuan1,2; Rajendran,Barani Kumar1,2; Bao,Jiaolin1,2; Zeng,Jianming1,2; Sun,Heng1,2; Chen,Ping1,2; Tan,Kaeling1,3; Chen,Qiang1,2; Wong,Koon Ho1,3; Xu,Xiaoling1,2,4; Deng,Chu Xia1,2
2020-12-01
Source PublicationNature Communications
Volume11Issue:1
AbstractBRCA1 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.
DOI10.1038/s41467-020-16936-9
URLView the original
Language英语
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Document TypeJournal article
CollectionUniversity of Macau
Affiliation1.Cancer Center,Faculty of Health Sciences,University of Macau,Macao
2.Centre for Precision Medicine Research and Training,Faculty of Health Sciences,University of Macau,Macao
3.Genomics & Bioinformatics Core,Faculty of Health Sciences,University of Macau,Macao
4.Transgenic and Knockout Core,Faculty of Health Sciences,University of Macau,Macao
First Author AffilicationFaculty of Health Sciences
Recommended Citation
GB/T 7714
Miao,Kai,Lei,Josh Haipeng,Valecha,Monica Vishnu,et al. NOTCH1 activation compensates BRCA1 deficiency and promotes triple-negative breast cancer formation[J]. Nature Communications,2020,11(1).
APA Miao,Kai.,Lei,Josh Haipeng.,Valecha,Monica Vishnu.,Zhang,Aiping.,Xu,Jun.,...&Deng,Chu Xia.(2020).NOTCH1 activation compensates BRCA1 deficiency and promotes triple-negative breast cancer formation.Nature Communications,11(1).
MLA Miao,Kai,et al."NOTCH1 activation compensates BRCA1 deficiency and promotes triple-negative breast cancer formation".Nature Communications 11.1(2020).
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