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BRD4 Regulates Breast Cancer Dissemination through Jagged1/Notch1 Signaling

Guillaume Andrieu1, Anna H Tran1, Katherine J Strissel1

  • 1Cancer Center, Boston University School of Medicine, Boston, Massachusetts.

Cancer Research
|September 22, 2016
PubMed

Insights

Bromodomain and extraterminal domain (BET) protein BRD4 drives triple-negative breast cancer invasion via the Jagged1/Notch1 pathway. Targeting BRD4 may inhibit cancer metastasis and progression.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Molecular Oncology

Background:

  • Bromodomain and extraterminal (BET) proteins are epigenetic readers involved in cancer.
  • Understanding individual BET protein roles is crucial for targeted cancer therapies.
  • JQ1 is a small molecule inhibitor targeting BET proteins.

Purpose of the Study:

  • To investigate the role of individual BET proteins in triple-negative breast cancer (TNBC) progression.
  • To identify signaling pathways regulated by BET proteins in TNBC.
  • To explore the therapeutic potential of targeting specific BET proteins in TNBC.

Main Methods:

  • Utilized BRD4-selective knockdown in TNBC cells.
  • Assessed Jagged1 expression and Notch1 signaling activity.
  • Investigated the impact of BRD4 on IL6-stimulated migration and invasion.
  • Correlated BRD4 and Jagged1 expression with patient metastasis data.

Main Results:

  • BRD4, not BRD2 or BRD3, regulated Jagged1 expression and Notch1 signaling in TNBC.
  • BRD4 knockdown suppressed Notch1 activity, impeding cancer cell migration and invasion.
  • BRD4 was essential for IL6-stimulated and Notch1-induced migration and invasion.
  • Elevated BRD4 and Jagged1 expression correlated with distant metastases in patients.

Conclusions:

  • A BRD4/Jagged1/Notch1 signaling pathway critically drives TNBC cell migration, invasion, and dissemination.
  • BRD4 plays a specific and essential role in TNBC progression.
  • This pathway represents a potential therapeutic target for inhibiting TNBC metastasis.

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