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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

CdGAP is required for transforming growth factor β- and Neu/ErbB-2-induced breast cancer cell motility and invasion

Y He1, J J Northey, M Primeau

  • 1Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.

Oncogene
|November 3, 2010
PubMed

Insights

Cdc42 GTPase-activating protein (CdGAP) is crucial for TGFβ-induced breast cancer cell motility and invasion. Downregulating CdGAP inhibits invasion and increases E-Cadherin, suggesting a role in the synergistic interaction between TGFβ and Neu/ErbB-2 signaling.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Rho GTPases regulate cellular functions; Cdc42 GTPase-activating protein (CdGAP) targets Cdc42 and Rac1.
  • CdGAP is involved in cell spreading and lamellipodia formation, regulated by the MEK-ERK pathway.
  • CdGAP expression is elevated in mammary tumors with activated Neu/ErbB-2.

Purpose of the Study:

  • To investigate the role of CdGAP in transforming growth factor-β (TGFβ)-induced cell motility and invasion in breast cancer.
  • To elucidate the functional domains of CdGAP essential for TGFβ-mediated cellular responses.
  • To understand the interplay between TGFβ and Neu/ErbB-2 signaling pathways involving CdGAP.

Main Methods:

  • Small interfering RNA (siRNA) to downregulate CdGAP expression.
  • Analysis of cell motility, invasion, adhesion, proliferation, and E-Cadherin expression.
  • TGFβ stimulation and Neu/ErbB-2 activation in mammary tumor explants and NMuMG cells.
  • Rescue experiments using CdGAP deletion-mutant proteins.

Main Results:

  • CdGAP downregulation abrogated TGFβ-induced cell motility and invasion but not adhesion.
  • Loss of CdGAP increased E-Cadherin expression and partially prevented epithelial to mesenchymal transition.
  • CdGAP depletion reduced cell proliferation independently of TGFβ.
  • The proline-rich domain (PRD) of CdGAP, not the GAP domain, was essential for TGFβ-induced motility and invasion.

Conclusions:

  • CdGAP is a novel molecular target in TGFβ signaling.
  • CdGAP is essential for TGFβ-induced cell motility and invasion in breast cancer cells.
  • CdGAP plays a key role in the synergistic interaction between TGFβ and Neu/ErbB-2 signaling pathways.

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