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

Important role of integrins in the cancer biology

“…Expression of α6β4 integrin is associated with aggressive and metastatic cancer. β4 integrin expression increases metastasis in MDA-MB-435 breast cancer cells [11]. Therefore, during invasion through the basement membrane, tumor cells frequently remodel the matrix through laminin deposition.…”

Mnk Mediates Integrin α6β4–Dependent eIF4E Phosphorylation and Translation of VEGF mRNA

“…Based on previous reports that expression of b4 integrin in MDA-MB-435 cells enhances their malignant behaviors (8,35,36), we assessed the impact of Mnk inhibition by CGP57380 on the proliferation of MDA-MB-435 mock and b4 cells (Fig. 3A).…”

Differential Expression of Cancer-Associated Fibroblast-Related Proteins in Ductal Carcinoma in situ According to Molecular Subtype and Stromal Histology

“…The functional pathways of genes of which expression increased in CAFs of HER-2 positive breast cancer were actin cytoskeleton signaling and integrin signaling. It has been reported that actin cytoskeleton signaling is associated with NG2 [29] and PDGFR [30], while integrin signaling is associated with S100A4 [31][32][33] and NG2 [34][35][36]. It has also been reported that molecular features that induce disease progression are different in each intrinsic molecular subtype of DCIS [24] and have an important role in the tumor microenvironment and progression of DCIS [37,38].…”