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Updated: Dec 17, 2025

Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer
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Published on: January 12, 2020

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

Kai Miao1,2, Josh Haipeng Lei1,2, Monica Vishnu Valecha1,2

  • 1Cancer Center, Faculty of Health Sciences, University of Macau, Macau, SAR, China.

Nature Communications
|June 28, 2020
PubMed

Insights

Targeting the NOTCH1-ATR-CHK1 pathway with cisplatin offers a new treatment for triple-negative breast cancer (TNBC). This combination therapy addresses cell cycle checkpoints, DNA damage, and epithelial-mesenchymal transition (EMT) in BRCA1-deficient tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • BRCA1 mutations increase triple-negative breast cancer (TNBC) risk.
  • TNBC is challenging due to resistance to targeted therapies.
  • The epithelial-mesenchymal transition (EMT) and cell cycle regulation are critical in TNBC.

Purpose of the Study:

  • Identify novel cancer drivers in Brca1-deficient mice.
  • Investigate the role of Notch1 in TNBC progression and therapeutic resistance.
  • Evaluate the efficacy of targeting the NOTCH1-ATR-CHK1 pathway in TNBC.

Main Methods:

  • Utilized the Sleeping Beauty transposon system in Brca1-deficient mouse models.
  • Analyzed 169 putative cancer drivers, focusing on Notch1.
  • Examined human TNBC tissues for NOTCH1 and ATR expression and phosphorylation.
  • Assessed the combined effect of NOTCH1 inhibition and cisplatin in TNBC models.

Main Results:

  • Identified 169 potential cancer drivers, with Notch1 as a key accelerator of TNBC.
  • NOTCH1 activation suppresses mitotic catastrophe by restoring cell cycle checkpoints via the ATR-CHK1 pathway.
  • NOTCH1 is highly expressed in human TNBC, correlating with increased ATR phosphorylation.
  • Combined inhibition of NOTCH1-ATR-CHK1 and cisplatin synergistically kills TNBC cells.

Conclusions:

  • NOTCH1 plays a crucial role in TNBC development and progression by promoting EMT and regulating cell cycle checkpoints.
  • The NOTCH1-ATR-CHK1 signaling pathway is a critical mediator of BRCA1-deficient breast cancer.
  • Targeting the NOTCH1-ATR-CHK1 cascade in combination with cisplatin presents a promising clinical strategy for treating TNBC.

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