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Short Communication |
§
From the Department of Pathology,*
Yale University
School of Medicine, New Haven, Connecticut and the Departments of
Internal Medicine,
Human
Genetics,
and
Pathology,§
Division of Molecular Medicine and
Genetics, University of Michigan School of Medicine, Ann
Arbor, Michigan
ß-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 3ß phosphorylation sites near the
ß-catenin amino terminus have been found in some cancers and cancer
cell lines. The mutations render ß-catenin resistant to regulation by
a complex containing the glycogen synthase kinase 3ß,
adenomatous polyposis coli, and axin proteins. As a
result, ß-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 ß-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
ß-catenin defects in primary melanomas, we undertook
immunohistochemical and DNA sequencing studies in 65 melanoma
specimens. Nuclear and/or cytoplasmic localization of
ß-catenin, a potential indicator of wnt
pathway activation, was seen focally within roughly one third
of the tumors, though a clonal somatic mutation in ß-catenin
was found in only one case (codon 45 Ser
Pro). Our findings
demonstrate that ß-catenin mutations are rare in primary
melanoma, in contrast to the situation in melanoma cell lines.
Nonetheless, activation of ß-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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