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Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer
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Cyclin D1 is a direct target of JAG1-mediated Notch signaling in breast cancer

Brenda Cohen1, Mamiko Shimizu, Julia Izrailit

  • 1Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, Canada.

Breast Cancer Research and Treatment
|November 17, 2009
PubMed

Insights

Jagged1 (JAG1) ligand drives triple-negative breast cancer growth by increasing cyclin D1 expression. Down-regulating JAG1 inhibits cancer cell proliferation, offering a potential therapeutic target for this aggressive breast cancer subtype.

Area of Science:

  • Oncology
  • Genomics
  • Molecular Biology

Background:

  • The Notch ligand, Jagged1 (JAG1), is implicated in breast cancer recurrence.
  • Triple-negative (TN) breast cancer exhibits distinct JAG1 expression patterns compared to other subtypes.

Purpose of the Study:

  • To investigate the downstream molecular mechanisms by which JAG1 promotes breast cancer growth.
  • To identify JAG1-regulated genes and pathways in TN breast cancer.

Main Methods:

  • Genomic analysis of 46 breast cancer cell lines to assess JAG1 expression.
  • RNA interference (siRNA) to down-regulate JAG1 in TN breast cancer cells.
  • Microarray profiling to identify JAG1-regulated genes.
  • Chromatin immunoprecipitation (ChIP) to assess Notch binding to the cyclin D1 promoter.

Main Results:

  • TN breast cancer cell lines express significantly higher JAG1 levels than HER2(+) or luminal subtypes.
  • JAG1 down-regulation inhibits TN breast cancer cell growth.
  • Cyclin D1 is identified as a direct target of NOTCH1 and NOTCH3, regulated by JAG1.
  • JAG1 down-regulation reduces Notch binding to the cyclin D1 promoter, decreases cyclin D1 expression, and inhibits cell cycle progression.

Conclusions:

  • JAG1 promotes proliferation in TN breast cancer through the JAG1-Notch-cyclin D1 pathway.
  • JAG1 and cyclin D1 expression are correlated in TN breast cancer datasets.
  • Targeting the JAG1-cyclin D1 axis represents a potential therapeutic strategy for TN breast cancer.

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