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

Masahiro Kai ,Jiaolin Bao,Xueying Lyu,Heng Sun,Jianming Zeng,Jun Xu,Zhengqiang Miao,Koon Ho Wong,Si Chen,Mónica Valecha ,Qiang Chen,Sek Man Su,Kaeling Tan,Xin Zhang,Fangyuan Shao,Ping Chen,Aiping Zhang,Lijian Wang,Xiaoling Xu,Josh Haipeng Lei,Barani Kumar Rajendran,Chu‐Xia Deng

doi:10.1038/s41467-020-16936-9

Masahiro Kai , Jiaolin Bao + Show 20 more

Open Access

https://doi.org/10.1038/s41467-020-16936-9

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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.

Highlights

Breast cancer gene 1 (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
We and others have demonstrated that complete knockout of Brca[1] in the whole body (Brca1−/−) causes lethality at embryonic day 7–8 (E7-8)[12,13]; in contrast, mammary-specific deletion of exon 11 of Brca[1] (Brca1Co/Co; MMTV-Cre) results in mammary tumour formation accompanied by massive genomic alterations and cellular lethality[14]
Brca1Co/Co;Wap-Cre (BrW, n = 62) mice and Brca1Co/Co;MMTV-Cre (BrM, n = 56) mice without the Sleeping Beauty (SB) transposase or transposon were used as controls (Supplementary Data 1)

Summary

Introduction

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. Studies have demonstrated that loss of BRCA1 results in defective DNA damage repair, abnormal centrosome duplication, G2-M cell-cycle checkpoint defects, growth retardation, increased apoptosis, genetic instability and tumourigenesis[9,10,11]. We and others have demonstrated that complete knockout of Brca[1] in the whole body (Brca1−/−) causes lethality at embryonic day 7–8 (E7-8)[12,13]; in contrast, mammary-specific deletion of exon 11 of Brca[1] (Brca1Co/Co; MMTV-Cre) results in mammary tumour formation accompanied by massive genomic alterations and cellular lethality[14] These findings prompted us to hypothesise that tumourigenesis triggered by Brca[1] deficiency must encounter a lethal block that retards tumour progression, at least in early stages. Brca[1] deficiency is a double-edged sword, i.e., genome instability dysregulates massive tumour suppressor and oncogenic factors to promote tumourigenesis, but too much DNA damage initiates a lethal block by inducing apoptosis to retard tumour formation

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