The syndecans are a family of heparan sulfate proteoglycans that function as receptors in extracellular matrix adhesion and growth factor signaling. Of the four family members, syndecan-1 is the most abundant on epithelial cells. The core protein of this receptor has a highly conserved but short cytoplasmic domain, a conserved transmembrane domain, and a more highly variable extracellular )rotein domain (ectodomain). Our recent work has identified several novel interactions of this core protein, showing that each of these discrete domains has unique activity. We plan to examine the unique activities that we have described for the cytoplasmic domain and extracellular domain in human nammary epithelial cells. We will examine the newly discovered role of the syndecan-1 ectodomain in activation of the ava3 integrin. This integrin is expressed on a number of invasive mammary carcinomas and its activated form leads to mammary carinoma cell metastases. We will attempt to define how syndecan-1 regulates the activity of this receptor, and define inhibitors to block its actvity. We will also examine the role of syndecan-1 in the activity of alphavbeta4 integrin. This integrin is critical for the normal polarized phenotype of mammary epithelial cells and their anchorage to their underlying basal lamina ich in laminin 5. However, the integrin is converted to a motility-signaling role on invasive cells. We wil examine how syndecan-1 participates in activity and thus contributes to the tumorigenic phenotype of transformed cells. Finally, we will assess normal and tumorigenic mammary epithelial cells in a three-dimensional matrigel culture, in which the cells display a phenotype more similar to that observed in vivo, and rely on signaling mechanisms differently that in common two-dimensional experiments. We will examine the role of syndecan-1 and the seemingly dramatic role that it has on human mammary epithelial cells in this environment. We will then extend these studies to a tumorigenesis model using the human carcinoma cells in SCID mice. We anticipate that completion of these studies will provide new and unexpected insights into the function of this receptor, and will lead to the development of new cancer treatments.
