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The FGF Receptor is a Target for N-Cadherin in Breast Cancer Invasion
N-cadherin, an adhesion molecule involved in dynamic processes such as cell migration and neurite outgrowth, is upregulated in breast cancer cell lines and promotes tumor invasion. In contrast, E-cadherin is often lost during metastasis and exerts anti-invasive effects on breast cancer cells. We and others have shown that N-cadherin can convert breast cancer cells from poorly to highly invasive and induces metastatic tumors even in the presence of E-cadherin. We have found that N-cadherin associates with and prevents internalization of the FGFR-1 leading to sustained MAPK, MMP-9 expression and tumor cell invasion. Interestingly, while FGF-2 and N-cadherin induced-invasion is regulated by MAPK signaling, cell motility is not, suggesting that, in this case, migration is governed by signaling pathways that are distinct from those that control invasion. We hypothesize N-cadherin still promotes invasion and metastasis even in the presence of the "suppressive" E-cadherin. We believe these two cadherins are fundamentally different with respect to their adhesive and non-adhesive regulatory functions. We have evidence that the opposite effects of N- and E-cadherin on tumor invasion may be due to differential effects of the two cadherins on FGFR stability. In addition, we propose that the signaling pathway (s) that govern migration by the N-cadherin-FGFR axis are distinct from those that control invasion. We will 1) identify the domains/residues present within N-cadherin that mediate FGFR stability and invasion, and 2) elucidate the signaling events that discriminate migration from invasion in response to N-cadherin and FGF-2. First, we will map the domains on N-cadherin that promote FGFR stability and interaction by deletion or point mutation. N-cadherin mutants that do not stabilize or interact with FGFR will be tested for invasive promoting activity. The invasion-promoting domain(s) from N-cadherin will be transplanted onto E-cadherin to determine if the domain is sufficient to convert a non-invasive to an invasion-promoting cadherin. Second, we will characterize the signaling pathways that mediate motility but not invasion and vice versa. We will inhibit well-defined signaling pathways and evaluate their effect on motility or invasion. Delineating the pathways that segregate migration from invasion induced by the N-cadherin-FGFR axis and finding the determinants on N-cadherin that support FGFR stability and tumor cell invasion will enhance our understanding of breast tumor metastasis and provide insights for blocking tumor metastasis.
Relatively little is known about the molecular aspects of breast cancer metastasis, which is in contrast to the vast knowledge on tumor cell growth. It had been hypothesized that for tumor cells to metastasize they must “lose” their interactions with other tumor cells, thus enabling tumor cells to detach from the primary tumor and spread to distant organs. We are now finding out, however, that rather than being a passive loss of cell adhesion, metastasis begins with an active shift in the adhesive specificity of the tumor cells. This shift involves the loss of one member of the cadherin family of adhesion molecules (E-cadherin) and the gain of another cadherin (N-cadherin). In the course of investigating the loss of E-cadherin adhesion in tumor cells we found that N-cadherin, was upregulated in the most invasive breast cancer cell lines. This pattern was exactly opposite to that of E-cadherin which was found only in the least invasive cells. This finding changed the prevailing hypothesis that tumor cells merely lose their adhesive strength on their way to metastasis. Rather, we proposed, the adhesiveness of tumor cells shifts from a stable, epithelial-type adhesion promoted by E-cadherin towards a more dynamic type of adhesion mediated by N-cadherin. We have recently shown that expression of N-cadherin in non-invasive E-cadherin expressing breast cancer cell lines increased their migratory and invasive/metastatic potential. Furthermore, we found that N-cadherin exerts its invasive action by interacting with the fibroblast growth factor receptor by increasing its life span and signaling potential. This results in the production of proteases that degrade basement membranes, allowing for metastatic spread of tumor cells. N-cadherin exerts its effects even in the presence of the “invasion suppressor” E-cadherin, further suggesting a dominant role for N-cadherin in metastasis. We plan to decipher the invasive function of N-cadherin by identifying the domain(s) on N-cadherin that stabilizes the FGFR protein to lead to enhanced FGFR signaling and tumor invasion. This information will help us identify the invasive moiety on N-cadherin that can be targeted for the design of reagents that could block metastasis in breast cancer. Furthermore, we will fine-map the signaling events that dissect migration from invasion induced by the N-cadherin-FGFR axis. This will give us a unique opportunity to identify potential targets that can either block the locomotion or the invasion of tumor cells, both of which are critical for metastatic dissemination.