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ErbB2 requires integrin alpha5 for anoikis resistance via Src regulation of receptor activity in human mammary

Keneshia K Haenssen1, Sarah A Caldwell, Kristina S Shahriari

  • 1Department of Biochemistry and Molecular Biology, 245 N 15 Street, Drexel University College of Medicine, Philadelphia, PA 19102, USA.

Journal of Cell Science
|March 25, 2010
PubMed

Insights

ErbB2 overexpression promotes cancer cell survival by upregulating integrin alpha5, which mediates anoikis resistance and inhibits Bim. This pathway, involving Src, offers a potential therapeutic target in ErbB2-positive tumors.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Signaling

Background:

  • ErbB2 (a receptor tyrosine kinase) is highly expressed in many tumors and inhibits apoptosis.
  • ErbB2 overexpression leads to anoikis resistance, contributing to tumor progression.
  • Integrins and growth factor receptors exhibit functional interdependence.

Purpose of the Study:

  • To investigate the role of integrin subunits in ErbB2-mediated survival signaling.
  • To elucidate the mechanism by which ErbB2 confers anoikis resistance.

Main Methods:

  • Utilized MCF-10A cells overexpressing ErbB2 in three-dimensional acinar cultures.
  • Examined integrin alpha5 upregulation via the MAP-kinase pathway.
  • Assessed the impact of integrin alpha5 depletion on ErbB2 signaling and anoikis resistance.
  • Investigated the interplay between integrin alpha5, Src, and ErbB2 phosphorylation.

Main Results:

  • ErbB2 overexpression upregulates integrin alpha5 through the MAP-kinase pathway.
  • Elevated integrin alpha5 levels correlate with ErbB2 status in human breast cancer.
  • Integrin alpha5 is essential for ErbB2-mediated anoikis resistance and Bim inhibition.
  • Integrin alpha5 mediates Src and ErbB2 survival signaling in low-adhesion states.

Conclusions:

  • Integrin alpha5 is a critical mediator of ErbB2-driven survival signaling in low-adhesion conditions.
  • Blocking Src activity during cell detachment reverses ErbB2-mediated survival.
  • The identified integrin alpha5-Src-ErbB2 pathway is a potential therapeutic target for ErbB2-positive tumors.

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