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Identification of the EBF1/ETS2/KLF2-miR-126-Gene Feed-Forward Loop in Breast Carcinogenesis and Stemness

Alessandra Gambacurta1,2, Valentina Tullio1, Isabella Savini1

  • 1Department of Experimental Medicine, Tor Vergata University of Rome, 00133 Rome, Italy.

International Journal of Molecular Sciences
|January 11, 2025
PubMed

Insights

Early B Cell Factor 1 (EBF1), ETS Proto-Oncogene 2 (ETS2), and Krüppel-Like Factor 2 (KLF2) regulate microRNA-126 (miR-126) in breast cancer (BC). Their downregulation disrupts a feed-forward loop, promoting BC progression.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • MicroRNA (miR)-126 exhibits tumor-suppressive functions and is often downregulated in breast cancer (BC).
  • The precise mechanisms driving miR-126 downregulation in BC remain largely unknown.
  • Understanding these mechanisms is crucial for developing targeted BC therapies.

Purpose of the Study:

  • To elucidate the molecular mechanisms behind miR-126 downregulation in breast cancer.
  • To identify key transcription factors regulating miR-126 expression.
  • To investigate the role of the identified regulatory network in BC progression.

Main Methods:

  • Silencing experiments were performed to identify regulatory transcription factors.
  • Gene Ontology analysis was used to analyze differentially expressed miR-126 target genes in the TCGA-BRCA cohort.
  • Interconnections between transcription factors, miR-126, and target genes were mapped.

Main Results:

  • Early B Cell Factor 1 (EBF1), ETS Proto-Oncogene 2 (ETS2), and Krüppel-Like Factor 2 (KLF2) were identified as critical regulators of miR-126 expression.
  • These transcription factors are downregulated in BC via epigenetic silencing or repressed promoter states, leading to reduced miR-126 levels.
  • A feed-forward loop (FFL) involving EBF1/ETS2/KLF2 and miR-126 was identified, which is disrupted in BC, promoting oncogenesis.

Conclusions:

  • The EBF1/ETS2/KLF2/miR-126 axis and its associated FFL play a significant role in maintaining cellular identity and preventing stemness in BC.
  • Dysregulation of this axis promotes BC progression by impairing miR-126 function and fostering oncogenic transformation.
  • Targeting this regulatory network offers potential therapeutic strategies for breast cancer management.
Keywords:
bioinformaticsbreast cancerepigeneticsmicroRNAsneural stemnesstranscription factors

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