Nuclear β-catenin in basal cell carcinoma correlates with increased proliferation

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SummaryBackgroundVirtually all BCCs have deregulation of the Hedgehog (Hh) signalling pathway and a proportion show nuclear β-catenin accumulation. The latter is thought to be due to Hh pathway-directed Wnt expression but this has not been tested. An alternative cause of nuclear β-catenin accumulation is gene mutation, which stabilizes the protein. Theoretically, reduced E-cadherin expression could also be important because it can sequester β-catenin at the cell membrane. In turn, nuclear β-catenin can increase expression of MYC and cyclin D1, thus potentially altering proliferation.ObjectivesTo assess whether nuclear β-catenin occurs in BCC, and to look at potential causes and consequences.MethodsNuclear β-catenin was assessed by immunohistochemistry, and its causes by analysis of E-cadherin expression, β-catenin exon 3 mutation and WNT5A expression. Its consequences were assessed by analysing proliferation.ResultsWe found nuclear β-catenin in 20 of 86 paraffin-embedded sections of BCCs using immunohistochemistry. BCCs showed increased WNT5A relative to the surrounding skin. No mutations in exon 3 of the β-catenin gene were found in 10 cases. There was no association between β-catenin localization and E-cadherin expression. Tumours with nuclear β-catenin had significantly higher proliferation (P < 0·01).ConclusionsThe absence of β-catenin gene mutations indicate that the Hh pathway-directed Wnt signalling remains the most likely cause of nuclear β-catenin accumulation in BCC. Additionally, the correlation with increased proliferation is the first evidence that nuclear β-catenin may have a biological effect. However, a causal link between Hh pathway deregulation, Wnt ligand overexpression, nuclear β-catenin accumulation and increased proliferation remains to be confirmed.

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