In addition to epithelial cancer, we are also interested in the role of cadherins in brain development and disease. Brain-specific cadherins play important roles in axonal pathfinding and neurite extension. Early reports suggest that the p120-binding region of these cadherins mediates their effects, while Rho GTPases are known to affect axonal pathfinding and neurite extension. In addition, recent experiments in knockout animals suggest that p120 family members are important for learning and memory, while kaiso, the p120-associated transcription factor plays important roles in brain development, as well as the expression of catecholamine neurotransmitters. Interestingly, unlike p120, the other p120 family members exhibit a more restricted expression pattern, suggesting that they have specialized functions. These proteins are all expressed in neuronal tissues and are thought to play important roles in spine morphogenesis and neuronal function.
Since all of the p120 family members share the ability to affect Rho GTPases, it is also likely that these proteins affect neuronal or glial cell migration associated with normal brain morphogenesis, or brain tumor spread. We are currently testing the latter hypothesis, by investigating the role of the cadherin/catenin system in human gliomas, a type of tumor that is difficult to treat particularly because of the increased tumor spread. Finally, we are also investigating the possibility that elevated neuronal cadherin expression in Her2-overexpressing breast cancer cells mediates the increased metastatic potential of these cells to brain.
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