Role of Integrin Alpha 5 in ErbB2-Mediated Breast Cancer
Annual summary rept. 1 Sep 2008-31 Aug 2009
DREXEL UNIV PHILADELPHIA PA
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We show that MCF-10A cells overexpressing ErbB2 upregulate integrin alpha5 via the MAPK pathway in 3D acini and found elevated integrin alpha5 levels associated with ErbB2 status in human breast cancer. Moreover, 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 Tyr-877 and ErbB2 phosphorylation is associated with increased activity of c-Src in the absence of cell adhesion. We show that blocking elevated c-Src activity during cell detachment reverses ErbB2-mediated survival and Bim repression. Integrin alpha5 serves as a key mediator of c-Src and ErbB2-survival signaling under states of low adhesion necessary to block the pro-anoikis mediator Bim and suggest this pathway represents a potential novel therapeutic target in ErbB2-positive tumors to reverse anoikis resistance.
- Anatomy and Physiology
- Medicine and Medical Research