GATA3 suppresses metastasis and modulates the tumour microenvironment by regulating microRNA-29b expression

Nat Cell Biol. 2013 Feb;15(2):201-13. doi: 10.1038/ncb2672. Epub 2013 Jan 27.

Abstract

Despite advances in our understanding of breast cancer, patients with metastatic disease have poor prognoses. GATA3 is a transcription factor that specifies and maintains mammary luminal epithelial cell fate, and its expression is lost in breast cancer, correlating with a worse prognosis in human patients. Here, we show that GATA3 promotes differentiation, suppresses metastasis and alters the tumour microenvironment in breast cancer by inducing microRNA-29b (miR-29b) expression. Accordingly, miR-29b is enriched in luminal breast cancers and loss of miR-29b, even in GATA3-expressing cells, increases metastasis and promotes a mesenchymal phenotype. Mechanistically, miR-29b inhibits metastasis by targeting a network of pro-metastatic regulators involved in angiogenesis, collagen remodelling and proteolysis, including VEGFA, ANGPTL4, PDGF, LOX and MMP9, and targeting ITGA6, ITGB1 and TGFB, thereby indirectly affecting differentiation and epithelial plasticity. The discovery that a GATA3-miR-29b axis regulates the tumour microenvironment and inhibits metastasis opens up possibilities for therapeutic intervention in breast cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / secondary
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Movement*
  • Female
  • GATA3 Transcription Factor / genetics
  • GATA3 Transcription Factor / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks
  • Genotype
  • Humans
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / prevention & control
  • Lung Neoplasms / secondary
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / metabolism*
  • Neoplasm Invasiveness
  • Phenotype
  • Transfection
  • Tumor Microenvironment*
  • Up-Regulation

Substances

  • GATA3 Transcription Factor
  • GATA3 protein, human
  • Gata3 protein, mouse
  • MIRN29 microRNA, human
  • MIRN29 microRNA, mouse
  • MicroRNAs