Frequent Nuclear/Cytoplasmic localization of beta-catenin without exon 3 mutations in malignant melanoma

beta-Catenin has a critical role in E-cadherin-mediated cell-cell adhesion, and it also functions as a downstream signaling molecule in the wnt pathwa y. Mutations in the putative glycogen synthase kinase 3 beta phosphorylatio n sites near the beta-catenin amino terminus have been found in some cancer s and cancer cell lines, The mutations render beta-catenin resistant to reg ulation by a complex containing the glycogen synthase kinase 3 beta, adenom atous polyposis coli, and axin proteins. As a result, beta-catenin accumula tes in the cytosol and nucleus and activates T-cell factor/lymphoid enhanci ng factor transcription factors. Previously, 6 of 27 melanoma cell lines we re found to have beta-catenin exon 3 mutations affecting the N-terminal pho sphorylation sites (Rubinfeld B, Robbins P, Elgamil M, Albert I, Porfiri E, Polakis P: Stabilization of beta-catenin by genetic defects in melanoma ce ll lines. Science 1997, 275:1790-1792). To assess the role of beta-catenin defects in primary melanomas, we undertook immunohistochemical and DNA sequ encing studies in 65 melanoma specimens. Nuclear and/or cytoplasmic localiz ation of beta-catenin, a potential indicator of wnt pathway activation, was seen focally within roughly one third of the tumors, though a clonal somat ic mutation in beta-catenin was found in only one case (codon 45 Ser-->Pro) . Our findings demonstrate that beta-catenin mutations are rare in primary melanoma, in contrast to the situation in melanoma cell lines. Nonetheless, activation of beta-catenin, as indicated by its nuclear and/or cytoplasmic localization, appears to be frequent in melanoma, and in some cases, it ma y reflect focal and transient activation of the wnt pathway within the tumo r.