A critical problem in management of melanoma is prediction of metastatic potential. The primary step in metastasis is release of adhesion. Beta-catenin is a critical component of the adhesive complex that also plays a role in signal transduction in development. Recently it has been discovered that beta-catenin is mutated in melanoma cell lines. These mutations cluster around the N-terminal serine and threonine phosphorylation sites and result in activation of beta-catenin in signal transduction in the wnt (wingless) pathway due to loss of APC (Adenomatous Polyposis Coli) mediated degradation. The activation of the wnt pathway in normal tissue plays a role in embryonic development mediating cell migration resulting in axial formation and development of the central -nervous system. Inappropriate activation of these mechanisms of motility (and invasion) in tumors most likely represents a step in the multi-step pathway of oncogenesis that portends more aggressive behavior. The finding of mutations in beta-catenin in melanoma cell lines prompted our examination of human malignant melanoma tissue specimens. We examined 81 metastatic tumors but found only one mutation at the critical phosphorylation sites. However, nuclear localization of beta-catenin, an indictor of activation of the wnt pathway, was seen in nearly one third of the cases. Our tentative conclusion is that activation of wnt, as assessed by nuclear beta-catenin, is a frequent event in melanoma. Since beta-catenin also plays a critical role in adhesion, it seems likely that activation of this pathway could effect outcome with respect to metastasis. Thus we hypothesize that alteration of beta-catenin will be a useful method to assess the aggressive nature and progression of malignant melanoma. In this pilot we propose a two-fold assessment of the role of beta-catemin in melanoma including; 1) to use a normal melanocyte cell line model to determine how these mutations in beta-catenin manifest their oncogenicity; and 2) to determine if there is an association between activation of the wnt pathway, as assessed by nuclear localization of beta-catenin, and melanoma stage, depth of invasion, and outcome.
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