[HTML][HTML] Loss of membranous expression of β-catenin is associated with tumor progression in cutaneous melanoma and rarely caused by exon 3 mutations

A Demunter, L Libbrecht, H Degreef, D Wolf-Peeters… - Modern …, 2002 - nature.com
A Demunter, L Libbrecht, H Degreef, D Wolf-Peeters, JJ van den Oord
Modern Pathology, 2002nature.com
Abstract β-Catenin plays a fundamental role in the regulation of the E-cadherin–catenin cell
adhesion complex. It also plays a role in the Wnt signaling pathway by activating T-cell factor–
and lymphoid enhancer factor–regulated gene transcription. The level of β-catenin in cells is
tightly controlled in a multiprotein complex, and mutations in the glycogen synthase kinase
3β (GSK-3β) phosphorylation sites of the β-catenin gene (CTNNB1) result in nuclear and/or
cytoplasmic accumulation of β-catenin and constitutive transactivation of T-cell factor and …
Abstract
β-Catenin plays a fundamental role in the regulation of the E-cadherin–catenin cell adhesion complex. It also plays a role in the Wnt signaling pathway by activating T-cell factor–and lymphoid enhancer factor–regulated gene transcription. The level of β-catenin in cells is tightly controlled in a multiprotein complex, and mutations in the glycogen synthase kinase 3β (GSK-3β) phosphorylation sites of the β-catenin gene (CTNNB1) result in nuclear and/or cytoplasmic accumulation of β-catenin and constitutive transactivation of T-cell factor and lymphoid enhancer factor target genes, a mechanism occurring in many cancers. Melanoma cell lines may harbor β-catenin mutations; in vivo, however, cellular accumulation of β-catenin is rarely caused by CTNNB1 mutations. In our study, 43 primary cutaneous melanoma and 30 metastases were screened for CTNNB1 exon 3 mutations by using a denaturing gradient gel electrophoresis technique and sequencing. β-Catenin mutations were found in 2 primary melanomas and 1 metastatic melanoma and were not correlated with nuclear accumulation of β-catenin in these cases. Cellular expression of β-catenin was evaluated by immun-ohistochemistry and by reverse polymerase chain reaction (RT-PCR) in 80 and 70 cases, respectively. Immunohistochemistry revealed a significant loss of membranous β-catenin staining between the primary and metastatic melanomas as well as between radial and vertical growth phase. RT-PCR showed a significant inverse correlation between the amount of RNA and the proportion of cells with membranous expression of β-catenin (P=. 0015); no correlation existed between the amount of RNA and the number of cells with nuclear or cytoplasmic expression of β-catenin. In conclusion, nuclear expression of β-catenin is seen in cutaneous melanoma but, in contrast to the case of many other cancers, does not correlate with tumor stage or mutation status. A combination of immunohistochemistry and RT-PCR showed that down-regulation of membranous β-catenin was associated with an increased amount of β-catenin RNA in primary or metastatic melanoma. Our results suggest that posttranslational events, rather than CTNNB1 mutations, are responsible for the altered distribution of β-catenin in cutaneous melanoma.
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