Loss of Membranous Expression of b-Catenin Is Associated with Tumor Progression in Cutaneous Melanoma and Rarely Caused by Exon 3 Mutations

• Published in: Modern pathology 2002-04, Vol.15 (4), p.454-461
• Main Authors: Demunter, Anouk, Libbrecht, Louis, Degreef, Hugo, De Wolf-Peeters, Chris, van den Oord, Joost J
• Format: Article
• Language: English
• ISSN: 0893-3952
• DOI: 10.1038/modpathol.3880546

b-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 b-catenin in cells is tightly controlled in a multiprotein complex, and mutations in the glycogen synthase kinase 3b (GSK-3b) phosphorylation sites of the b-catenin gene (CTNNB1) result in nuclear and/or cytoplasmic accumulation of b-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 b-catenin mutations; in vivo, however, cellular accumulation of b-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. b-Catenin mutations were found in 2 primary melanomas and 1 metastatic melanoma and were not correlated with nuclear accumulation of b-catenin in these cases. Cellular expression of b-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 b-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 b-catenin (P = .0015); no correlation existed between the amount of RNA and the number of cells with nuclear or cytoplasmic expression of b-catenin. In conclusion, nuclear expression of b-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 b-catenin was associated with an increased amount of b-catenin RNA in primary or metastatic melanoma. Our results suggest that posttranslational events, rather than CTNNB1 mutations, are responsible for the altered distribution of b-catenin in cutaneous melanoma.Mod Pathol 2002; 15(4):454-461