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Updated: Jul 7, 2026

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
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Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells

Published on: October 27, 2020

Altered TAB1:I kappaB kinase interaction promotes transforming growth factor beta-mediated nuclear factor-kappaB

Jason R Neil1, William P Schiemann

  • 1Department of Pharmacology, University of Colorado Health Sciences Center, Aurora, CO 80045, USA.

Cancer Research
|March 5, 2008
PubMed

Insights

Transforming growth factor beta (TGF-beta) switches from tumor suppressor to promoter in breast cancer by activating nuclear factor-kappaB (NF-kappaB) via a novel TAB1:TAK1:IKK beta pathway, driving tumor growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Transforming growth factor beta (TGF-beta) paradoxically acts as both a tumor suppressor and promoter during mammary tumorigenesis.
  • The molecular mechanisms driving this switch in TGF-beta's function remain largely undefined, particularly concerning its interaction with key signaling pathways.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which TGF-beta transitions from a tumor suppressor to a tumor promoter in breast cancer.
  • To identify the specific signaling axis responsible for TGF-beta's oncogenic activity in malignant mammary cells.

Main Methods:

  • Investigated TGF-beta's effect on nuclear factor-kappaB (NF-kappaB) activity in normal (NMuMG) and malignant (4T1) breast cells.
  • Analyzed the assembly of TGF-beta-activated kinase 1 (TAK1)-binding protein 1 (TAB1):I kappaB kinase beta (IKK beta) complexes.
  • Utilized a truncated TAB1 mutant (TAB1(411)) and small interfering RNA (siRNA) targeting TAK1 to assess pathway function.
  • Assessed tumor growth in mouse models (syngeneic BALB/c and nude mice).

Main Results:

  • TGF-beta repressed NF-kappaB in normal cells but activated it in malignant 4T1 cells via TAB1:IKK beta complex formation and a TAK1:IKK beta:p65 pathway.
  • TAB1:IKK beta complexes were induced during TGF-beta-mediated epithelial-mesenchymal transition (EMT) in NMuMG cells, activating NF-kappaB.
  • TAB1(411) expression inhibited NF-kappaB activation and downstream targets (TNF-alpha, COX-2) in response to TGF-beta.
  • TAK1 and NF-kappaB activities were essential for TGF-beta-induced invasion in MCF10A-CA1a cells.
  • TAK1 deficiency restored TGF-beta's cytostatic activity.
  • TAB1(411) expression significantly reduced 4T1 tumor growth in mice.

Conclusions:

  • A novel signaling axis involving TAB1:TAK1:IKK beta:NF-kappaB is aberrantly activated in breast cancer cells.
  • This aberrant signaling enables oncogenic TGF-beta signaling, promoting tumor progression and growth.
  • Targeting this pathway holds potential for therapeutic intervention in breast cancer.

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