[HTML][HTML] Frequent nuclear/cytoplasmic localization of β-catenin without exon 3 mutations in malignant melanoma

DL Rimm, K Caca, G Hu, FB Harrison… - The American journal of …, 1999 - Elsevier
DL Rimm, K Caca, G Hu, FB Harrison, ER Fearon
The American journal of pathology, 1999Elsevier
β-Catenin has a critical role in E-cadherin-mediated cell-cell adhesion, and it also functions
as a downstream signaling molecule in the wnt pathway. Mutations in the putative glycogen
synthase kinase 3β phosphorylation sites near the β-catenin amino terminus have been
found in some cancers and cancer cell lines. The mutations render β-catenin resistant to
regulation by a complex containing the glycogen synthase kinase 3β, adenomatous
polyposis coli, and axin proteins. As a result, β-catenin accumulates in the cytosol and …
β-Catenin has a critical role in E-cadherin-mediated cell-cell adhesion, and it also functions as a downstream signaling molecule in the wnt pathway. Mutations in the putative glycogen synthase kinase 3β phosphorylation sites near the β-catenin amino terminus have been found in some cancers and cancer cell lines. The mutations render β-catenin resistant to regulation by a complex containing the glycogen synthase kinase 3β, adenomatous polyposis coli, and axin proteins. As a result, β-catenin accumulates in the cytosol and nucleus and activates T-cell factor/lymphoid enhancing factor transcription factors. Previously, 6 of 27 melanoma cell lines were found to have β-catenin exon 3 mutations affecting the N-terminal phosphorylation sites (Rubinfeld B, Robbins P, Elgamil M, Albert I, Porfiri E, Polakis P: Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science 1997, 275:1790–1792). To assess the role of β-catenin defects in primary melanomas, we undertook immunohistochemical and DNA sequencing studies in 65 melanoma specimens. Nuclear and/or cytoplasmic localization of β-catenin, a potential indicator of wnt pathway activation, was seen focally within roughly one third of the tumors, though a clonal somatic mutation in β-catenin was found in only one case (codon 45 Ser→Pro). Our findings demonstrate that β-catenin mutations are rare in primary melanoma, in contrast to the situation in melanoma cell lines. Nonetheless, activation of β-catenin, as indicated by its nuclear and/or cytoplasmic localization, appears to be frequent in melanoma, and in some cases, it may reflect focal and transient activation of the wnt pathway within the tumor.
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