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

Abstract Integrin α6β4 is linked to cancer cell motility and invasion in aggressive and metastatic cancer cells. In this study, we showed that expression of the β4 integrin in MDA-MB-435 cancer cells (MDA-MB-435/β4) 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 β4 integrin expression in MDA-MB-231 breast carcinoma cells by shRNA reduced the level of S100A4 expression. The mechanism by which α6β4 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 β4 integrin subunit, is essential for α6β4-dependent S100A4 expression. Reduction of S100A4 expression by shRNA blocked migration, invasion, and anchorage-independent growth of MDA-MB-435/β4, SUM-159, and MDA-MB-231 cells. These studies define a novel mechanism by which integrin α6β4 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)