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Updated: Aug 25, 2026

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
06:54

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

Published on: October 27, 2020

Overexpression of HER2 (erbB2) in human breast epithelial cells unmasks transforming growth factor beta-induced cell

Yukiko Ueda1, Shizhen Wang, Nancy Dumont

  • 1Department of Medicine, Vanderbilt University School of Medicine, Vanderbilt-Ingram Comprehensive Cancer Center, Nashville, Tennessee 37232, USA.

The Journal of Biological Chemistry
|March 27, 2004
PubMed

Insights

Overexpression of human epidermal growth factor receptor 2 (HER2) enables transforming growth factor-beta (TGF-beta) to increase mammary cell motility. HER2 and TGF-beta signaling cooperate in cellular events linked to tumor progression.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Human epidermal growth factor receptor 2 (HER2) is a key oncogene in breast cancer.
  • Transforming growth factor-beta (TGF-beta) signaling plays complex roles in cell proliferation and motility.
  • Understanding the interplay between HER2 and TGF-beta is crucial for cancer progression insights.

Purpose of the Study:

  • To investigate how HER2 overexpression affects TGF-beta's anti-proliferative and motility-inducing effects.
  • To elucidate the signaling pathways involved in the cooperation between HER2 and TGF-beta.
  • To determine the therapeutic potential of targeting HER2 in TGF-beta-mediated processes.

Main Methods:

  • Overexpression of HER2 in MCF-10A human mammary epithelial cells.
  • Treatment with TGF-beta and assessment of cell proliferation and Smad-dependent reporter activity.
  • Wound closure and transwell assays to evaluate cell motility.
  • Inhibition studies using trastuzumab (Herceptin), ALK5(T204D), kinase inhibitors, and blocking antibodies.
  • Analysis of Rac1 activity and protein-protein interactions.

Main Results:

  • TGF-beta inhibited proliferation but induced motility in HER2-overexpressing cells.
  • HER2 overexpression enhanced TGF-beta-induced Smad-dependent transcriptional reporter activity.
  • Trastuzumab (Herceptin) blocked TGF-beta-induced cell motility.
  • TGF-beta-induced motility involved phosphatidylinositol 3-kinase, MAPK, and integrin beta(1) pathways.
  • HER2 constitutively associated with Rac1 and Pak1; TGF-beta and activated ALK5 enhanced this association.
  • Herceptin blocked Rac1 activity but not TGF-beta-stimulated transcription.

Conclusions:

  • HER2 overexpression is permissive for TGF-beta to induce cell motility and Rac1 activity in mammary epithelial cells.
  • HER2 and TGF-beta signaling pathways cooperate to promote cellular events associated with tumor progression.
  • Targeting HER2 may offer a strategy to inhibit TGF-beta-driven motility and potentially tumor progression.

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