Integrin (α6β4) Signals Through Src to Increase Expression of S100A4, a Metastasis-Promoting Factor: Implications for Cancer Cell Invasion

Integrin alpha 6 beta 4 is linked to cancer cell motility and invasion in aggressive and metastatic cancer cells. In this study, we showed that expression of the beta 4 integrin in MDA-MB-435 cancer cells (MDA-MB-435/beta 4) leads to a dramatic increase in expression of a metastasis-promoting factor, S100A4, as determined by affymetrix gene chip microarray, quantitative real-time PCR, and Western blot analysis. Alternatively, knocking down beta 4 integrin expression In MDA-MB-231 breast carcinoma cells by shRNA reduced the level of S100A4 expression. The mechanism by which alpha 6 beta 4 enhances S100A4 expression involves Src, Akt, and NFAT. We have further shown that Y1494, a tyrosine residue of the ITIM motif in the cytoplasmic domain of the beta 4 integrin subunit, is essential for alpha 6 beta 4-dependent S100A4 expression. Reduction of S100A4 expression by shRNA blocked migration, invasion, and anchorage-independent growth of MDA-MB-435/beta 4, SUM-159, and MDA-MB-231 cells. These studies define a novel mechanism by which Integrin alpha 6 beta 4 promotes cancer cell motility and invasion, and provides insight into how S100A4 expression is regulated In cancer cells. (Mol Cancer Res 2009;7(10):1605-12)