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.

BRCA1突变携带者罹患三阴性乳腺癌（TNBC）的风险更高，这是一种难治性疾病，因为它对当前的临床靶向疗法无反应。使用Brca1缺陷小鼠的Sleeping Beauty转座子系统，我们确定了169个推定的癌症驱动器，其中Notch1通过促进上皮-间质转化（EMT）和调节细胞周期，是促进TNBC的最佳人选。NOTCH1的激活可通过恢复S / G2和G2 / M细胞周期检查点来抑制BRCA1缺乏引起的有丝分裂灾难，这可能是通过激活ATR-CHK1信号通路来实现的。一致地，对人乳腺癌组织的分析表明，NOTCH1在TNBC中高度表达，并且NOTCH1的活化形式与ATR磷酸化呈正相关。此外，我们证明，通过靶向细胞周期检查点，DNA损伤和EMT，抑制NOTCH1-ATR-CHK1级联与顺铂协同杀伤TNBC，为这种致命疾病提供了有效的临床选择。