Breast cancer is the most frequently diagnosed cancer in females in the western world and breast cancer metastases are responsible for most

patient deaths. Syk, a non-receptor tyrosine kinase, recently was found to play a role to suppress metastatic breast cancer, which is interestingly different to its well-known-role in mediating hematopoetic cell proliferation, differentiation and phagocytosis. However the molecular mechanisms by which Syk functions as a tumor suppressor are far from defined. Syk contains two tandem SH2 domains and a kinase domain. Five phosphorylation sites and a nuclear localization signal have been identified on the protein. The interplay between cells and the extracellular matrix (ECM) through focal adhesions decides tumor cell motility, which is enhanced in metastatic breast cancer. We find that the expression of Syk enhances cell-cell interactions while inhibiting breast cancer cell motility. Syk’s kinase activity and phosphorylation on Y342 are important to inhibit cell motility. Cells expressing Syk spread faster than those expressing a catalytically inactive Syk or those deficient in Syk at 1 hour after being plated on fibronectin (FN), a main component of ECM. Furthermore, in these spreading cells, Syk partially relocalizes to the cell edge and colocalizes with F-actin. These data suggest that Syk modulates interactions between cells and the ECM to regulate cell motility. In fact, Syk is activated and induces additional protein phosphorylation in cells spreading on FN as well as in cells treated with an anti-integrin (FN receptor) antibody. Moreover, Syk’s kinase activity and phosphorylation site Y342 also are important for this integrin-stimulated pathway. Meanwhile both biochemical and immunofluorescence assays indicate a role for Syk in modulating the stability of the microtubule network, which is involved in integrin-signaling and the regulation of focal adhesion assembly and disassembly. These studies indicate that Syk suppresses malignant breast cancer cell motility by participating in an ECM/integrin-stimulated signaling pathway coupled to changes in the cellular cytoskeletal network.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA