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.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Miao K,Lei JH,Valecha MV,Zhang A,Xu J,Wang L,Lyu X,Chen S,Miao Z,Zhang X,Su SM,Shao F,Rajendran BK,Bao J,Zeng J,Sun H,Chen P,Tan K,Chen Q,Wong KH,Xu X,Deng CXdoi
10.1038/s41467-020-16936-9subject
Has Abstractpub_date
2020-06-26 00:00:00pages
3256issue
1issn
2041-1723pii
10.1038/s41467-020-16936-9journal_volume
11pub_type
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