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

Abstract

ErbB2, a receptor tyrosine kinase highly expressed in many tumors, is known to inhibit apoptotic signals. Overexpression of ErbB2 causes anoikis resistance that contributes to luminal filling in three-dimensional mammary epithelial acinar structures in vitro. Given that integrins and growth factor receptors are highly interdependent for function, we examined the role of integrin subunits in ErbB2-mediated survival signaling. Here, we show that MCF-10A cells overexpressing ErbB2 upregulate integrin alpha5 via the MAP-kinase pathway in three-dimensional acini and found elevated integrin alpha5 levels associated with ErbB2 status in human breast cancer. Integrin alpha5 is required for ErbB2-mediated anoikis resistance and for optimal ErbB2 signaling to the Mek-Erk-Bim axis as depletion of integrin alpha5 reverses anoikis resistance and Bim inhibition. Integrin alpha5 is required for full activation of ErbB2 tyrosine phosphorylation on Y877 and ErbB2 phosphorylation is associated with increased activity of Src in the absence of adhesion. Indeed, we show that blocking elevated Src activity during cell detachment reverses ErbB2-mediated survival and Bim repression. Thus, integrin alpha5 serves as a key mediator of Src and ErbB2-survival signaling in low adhesion states, which are necessary to block the pro-anoikis mediator Bim, and we suggest that this pathway represents a potential novel therapeutic target in ErbB2-positive tumors.

• Authors: Keneshia K Haenssen, Sarah A Caldwell, Kristina S Shahriari, S Raelle Jackson, Kelly A Whelan, Andres J Klein-Szanto, Mauricio J Reginato
• Journal: Journal of cell science (J Cell Sci) Vol. 123 Issue Pt 8 Pg. 1373-82 (Apr 15 2010) ISSN: 1477-9137 [Electronic] England
• PMID: 20332114 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Apoptosis Regulatory Proteins
• BCL2L11 protein, human
• Bcl-2-Like Protein 11
• Integrin alpha5
• Membrane Proteins
• Proto-Oncogene Proteins
• ERBB2 protein, human
• Receptor, ErbB-2
• src-Family Kinases
• Extracellular Signal-Regulated MAP Kinases
• Mitogen-Activated Protein Kinase Kinases

Topics

• Anoikis
• Apoptosis Regulatory Proteins (metabolism)
• Bcl-2-Like Protein 11
• Breast Neoplasms (enzymology, genetics, pathology)
• Cell Adhesion
• Cell Survival
• Enzyme Activation
• Epithelial Cells (enzymology)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Integrin alpha5 (genetics, metabolism)
• MAP Kinase Signaling System
• Mammary Glands, Human (cytology, growth & development)
• Membrane Proteins (metabolism)
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Morphogenesis
• Proto-Oncogene Proteins (metabolism)
• Receptor, ErbB-2 (metabolism)
• Up-Regulation (genetics)
• src-Family Kinases (metabolism)