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Opposing Functions of BRD4 Isoforms in Breast Cancer

Shwu-Yuan Wu1, Chien-Fei Lee2, Hsien-Tsung Lai2

  • 1Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Molecular Cell
|May 25, 2020
PubMed

Insights

The short isoform of Bromodomain-4 (BRD4-S) drives cancer, while the long isoform (BRD4-L) suppresses it. BRD4-S and Engrailed-1 regulate the extracellular matrix in breast cancer.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genomics

Background:

  • Bromodomain-containing protein 4 (BRD4) is a key regulator of transcription and a cancer therapeutic target.
  • The role of BRD4 in cancer has been primarily attributed to its long isoform (BRD4-L).

Purpose of the Study:

  • To investigate the distinct roles of BRD4-L and BRD4-S isoforms in breast cancer.
  • To identify key regulators and pathways modulated by oncogenic BRD4 isoforms.

Main Methods:

  • Isoform-specific knockdown and transgene expression.
  • Endogenous protein detection.
  • Integrated RNA-sequencing, ChIP-sequencing, and CUT&RUN profiling.

Main Results:

  • BRD4-S exhibits oncogenic activity, promoting breast cancer cell proliferation, migration, and metastasis.
  • BRD4-L demonstrates tumor-suppressive functions in breast cancer.
  • BRD4-S and Engrailed-1 (EN1) co-regulate the extracellular matrix (ECM) matrisome network, including specific gene clusters, in triple-negative breast cancer.

Conclusions:

  • BRD4-S is an oncogenic driver in breast cancer, distinct from the tumor-suppressive BRD4-L.
  • The BRD4-S/EN1 complex modulates ECM genes, highlighting a novel therapeutic vulnerability.
  • Targeted therapies should focus on the oncogenic activity of BRD4-S, sparing its tumor-suppressive functions.
Keywords:
BET inhibitorBRD4CUT&RUNECMTNBCbromodomaindrug resistanceenhancerepigeneticstranscription factor

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