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A p53/miR-30a/ZEB2 axis controls triple negative breast cancer aggressiveness

Alessandra di Gennaro1, Valentina Damiano1, Giulia Brisotto1

  • 1Oncogenetics and Functional Oncogenomics Unit, CRO Aviano National Cancer Institute, via F. Gallini 2, Aviano, 33081, PN, Italy.

Cell Death and Differentiation
|April 19, 2018
PubMed

Insights

p53 inactivation promotes aggressive breast cancer by reducing miR-30a, which normally suppresses ZEB2. This new p53/miR-30a/ZEB2 axis impacts tumor invasion and spread, particularly in triple-negative breast cancers (TNBCs).

Area of Science:

  • Molecular oncology
  • Cancer genetics
  • MicroRNA biology

Background:

  • p53 tumor suppressor inactivation is linked to poor breast cancer prognosis, especially in triple-negative breast cancers (TNBCs).
  • The mechanisms by which p53 loss drives tumor aggressiveness are not fully understood.
  • MicroRNAs (miRNAs) are implicated in cancer progression and may mediate p53's effects.

Purpose of the Study:

  • To investigate the role of miRNAs in the context of p53 inactivation in breast cancer.
  • To identify novel signaling pathways regulated by p53 involving miRNAs.
  • To elucidate the functional significance of the p53/miR-30a/ZEB2 axis in tumor behavior.

Main Methods:

  • In silico analysis to identify potential p53 targets.
  • Analysis of miRNA expression in breast tumors.
  • Luciferase reporter assays to confirm p53 binding to the MIR30A promoter.
  • Western blotting and qRT-PCR to assess protein and miRNA levels.
  • In vitro assays for cell migration, invasion, and drug resistance.

Main Results:

  • Reduced miR-30a expression correlates with p53 inactivation, lymph node positivity, and poor prognosis in breast tumors.
  • p53 directly binds the MIR30A promoter, inducing transcription of miR-30a.
  • miR-30a targets and represses ZEB2, a key regulator of epithelial-mesenchymal transition (EMT).
  • The p53/miR-30a/ZEB2 axis controls tumor cell invasion, metastasis, and influences miR-200c expression.

Conclusions:

  • A novel signaling axis, p53/miR-30a/ZEB2, is identified, linking p53 status to EMT.
  • p53 inactivation promotes tumor cell aggressiveness and spread through downregulation of miR-30a and subsequent ZEB2 upregulation.
  • This pathway is crucial for understanding TNBC progression and offers potential therapeutic targets.

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