"The basis of our research is the study of signalling molecules operative in malignant progression. Our approach has been to use both population based and laboratory approaches to answer overlapping biological questions. Our investigations uncovered that overexpression and amplificationof the HER2 receptor tyrosine kinase is associated with increased resistance to adjuvant chemotherapy. This inherent resistance is overcome by dose intensive chemotherapy. Given this finding, we sought to identify novel kinases associated with breast biology using degenerative PCR cloning. Our subsequent work showed that the transforming AXL receptor tyrosine kinase is associated with malignant breast epithelium, and is involved with adhesion and motogenesis. We have cloned the ligand, GAS6, and found that the GAS6/AXL interaction induces cell survival and cell migration. We are assessing the role of AXL and GAS6 in cancer cell invasion and breast development. In similar experiments we have identified a new G- coupled transmembrane receptor protein whose loss of expression is associated with a metastatic phenotype. Our current work centers on the function of this protein and the identification of its ligand. We have identified that the ability of the BRCA1 gene product is dependent on its association with a specific binding protein. This BRCA1 binding molecule is a component of the cell cycle machinery. Preliminary work suggests that this association is critical for the ability of BRCA1 to inhibit cellular growth. We have cloned a new kinase associated with growth cessation, called rak. This src related tyrosine kinase is homologous to the epithelial associated STK kinase in hydra and the drosophila DSRC41 gene. Our current information suggests that Rak is involved in epithelial differentiation."