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Discovery of epigenetically silenced tumour suppressor genes in aggressive breast cancer through a computational

Anne-Laure Vitte1, Florent Chuffart1, Emmanuelle Jacquet1,2

  • 1Université Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, 38000 Grenoble, France.

NAR Cancer
|June 30, 2025
PubMed

Insights

Aberrant activation of DNMT3B in breast cancer drives gene silencing and aggressive tumor behavior. GATA3 inactivation, through mutation or DNMT3B-driven hypermethylation, worsens prognosis, highlighting epigenetic targets for therapy.

Area of Science:

  • Oncology
  • Epigenetics
  • Genomics

Background:

  • Breast cancer involves genetic and epigenetic alterations leading to abnormal gene expression.
  • DNMT3B, a de novo DNA methyltransferase, is aberrantly activated in breast cancer, correlating with aggressive behavior and high relapse risk.
  • Previous research identified DNMT3B as a key player in breast cancer progression.

Purpose of the Study:

  • To investigate the role of DNMT3B in breast cancer by analyzing DNA methylation and transcriptomic data.
  • To identify genes downregulated by DNMT3B-driven hypermethylation and their association with relapse risk.
  • To explore the mechanisms of GATA3 inactivation and their impact on tumor progression and prognosis.

Main Methods:

  • Integrative bioinformatic analyses of DNA methylation and transcriptomic data.
  • Identification of genes downregulated by DNMT3B-driven promoter hypermethylation.
  • Analysis of GATA3 inactivation mechanisms (mutations vs. hypermethylation) and associated molecular signatures.

Main Results:

  • 154 genes were found to be downregulated via DNMT3B-driven promoter hypermethylation, many linked to high relapse risk.
  • GATA3 was identified as a primary target of inactivation through mutually exclusive mutations or DNMT3B-controlled hypermethylation.
  • Both GATA3 inactivation mechanisms correlated with tumor progression and poorer prognosis, with distinct immune/inflammation gene enrichment patterns observed.
  • Other potential tumor suppressor genes were found to be epigenetically repressed in aggressive breast cancers.

Conclusions:

  • GATA3 inactivation plays a significant role in aggressive breast cancer beyond genetic alterations, involving epigenetic mechanisms.
  • DNMT3B-driven hypermethylation contributes to tumor suppressor gene silencing in aggressive breast tumors.
  • Targeting epigenetically silenced tumor suppressors presents a potential therapeutic strategy for aggressive breast cancer.

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