Breast cancer metastasis depends on the ability of malignant cells to dissociate and migrate away from the primary tumor, to invade tissue barriers, and to disseminate through the vasculature and establish residence at distant sites. The cadherin family of adhesion molecules are emerging as important modulators of each of these processes. Highly invasive breast cancer cell lines do not express H- or E-cadherin in contrast to normal breast epithelial cells. Re-expression of either of these cadherins in malignant carcinomas reverses invasiveness. In vivo, H-cadherin, is downregulated in early carcinomas in situ while E-cadherin expression is lost in a later stage of tumor progression. The downregulation of both of these molecules in breast tumors is highly indicative of poor prognosis. In contrast to the apparent suppressive role of the above molecules, we have recently shown that another member of the cadherin family, N-cadherin, is upregulated in invasive breast tumor cell lines. N-cadherin-transfected breast cancer cells become more invasive in vitro and metastatic in vivo. Furthermore, N- cadherin mediated cell migration and invasion was potentiated by treatment of cells with FGF-2 and was associated with dramatic up-modulation of the matrix metalloproteinase, MMP-9. Our hypothesis is that the profile of cadherins changes with tumor progression and that growth factors, through their receptors, interact with specific cadherins to influence the invasion and metastasis of breast cancer cells. To investigate the mechanisms of the N-cadherin induced metastastic pathway in breast cancer we will test the effect of N-cadherin on FGFR expression, the interaction of FGF-2 with the receptor and the consequence this interaction may have on intracellular signaling and differential gene expression. We will test whether H-cadherin inhibits the invasion-promoting effects of N-cadherin both in vitro and in vivo. Finally, we will analyze the expression of the three cadherins and MMP-9 in breast tumor specimens at various stages of malignant progression to evaluate their efficacy as possible markers of survival and potential sites of therapeutic intervention.
