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Twist is transcriptionally induced by activation of STAT3 and mediates STAT3 oncogenic function

George Z Cheng1, Wei Zhou Zhang, Mei Sun

  • 1Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA.

The Journal of Biological Chemistry
|March 21, 2008
PubMed

Insights

Activated STAT3 (Signal Transducer and Activator of Transcription 3) drives Twist expression, a key factor in breast cancer metastasis. This STAT3-Twist pathway promotes cell migration and invasion, offering therapeutic targets for advanced tumors.

Area of Science:

  • Molecular Oncology
  • Cancer Biology
  • Signal Transduction

Background:

  • Metastasis is a critical hallmark of cancer progression.
  • Twist is a transcription factor implicated in epithelial-mesenchymal transition and metastasis.
  • Signal Transducer and Activator of Transcription 3 (STAT3) is frequently activated in various cancers.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying metastasis in human breast cancer.
  • To elucidate the role of STAT3 in regulating Twist expression and its contribution to invasive phenotypes.
  • To explore the STAT3-Twist signaling axis in clinical breast tumor samples.

Main Methods:

  • Comparison of gene expression and signaling pathways in low vs. high invasive breast cancer cell lines (MCF-7, MDA-MB453 and their invasive sublines).
  • Analysis of STAT3 phosphorylation, Twist protein and mRNA levels.
  • Functional assays including STAT3 inhibition (JSI-124, shRNA, dominant-negative), promoter binding studies, migration, invasion, and colony formation assays.
  • Analysis of STAT3 activation and Twist expression in clinical breast tissue specimens.

Main Results:

  • High invasive breast cancer sublines exhibited elevated STAT3 Tyr(705) phosphorylation and Twist expression.
  • STAT3 activation (via IL-6 or Src) induced Twist expression; STAT3 inhibition reduced Twist levels and cell invasion, migration, and colony formation.
  • STAT3 directly bound to the human Twist promoter, activating its transcription.
  • A strong correlation between Tyr(705) p-STAT3 and Twist levels was observed in late-stage tumor tissues.

Conclusions:

  • Activated STAT3 transcriptionally induces Twist, promoting key metastatic properties such as migration, invasion, and anchorage-independent growth.
  • The STAT3-Twist signaling axis is crucial for driving oncogenic functions in breast cancer.
  • STAT3, Twist, and AKT2 form a functional signaling axis regulating pivotal oncogenic properties, representing a potential therapeutic target.

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