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

Br J Dermatol. 2004 Jul;151(1):157-64. doi: 10.1111/j.1365-2133.2004.06048.x.

Abstract

Background: Virtually all BCCs have deregulation of the Hedgehog (Hh) signalling pathway and a proportion show nuclear beta-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 beta-catenin accumulation is gene mutation, which stabilizes the protein. Theoretically, reduced E-cadherin expression could also be important because it can sequester beta-catenin at the cell membrane. In turn, nuclear beta-catenin can increase expression of MYC and cyclin D1, thus potentially altering proliferation.

Objectives: To assess whether nuclear beta-catenin occurs in BCC, and to look at potential causes and consequences.

Methods: Nuclear beta-catenin was assessed by immunohistochemistry, and its causes by analysis of E-cadherin expression, beta-catenin exon 3 mutation and WNT5A expression. Its consequences were assessed by analysing proliferation.

Results: We found nuclear beta-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 beta-catenin gene were found in 10 cases. There was no association between beta-catenin localization and E-cadherin expression. Tumours with nuclear beta-catenin had significantly higher proliferation (P < 0.01).

Conclusions: The absence of beta-catenin gene mutations indicate that the Hh pathway-directed Wnt signalling remains the most likely cause of nuclear beta-catenin accumulation in BCC. Additionally, the correlation with increased proliferation is the first evidence that nuclear beta-catenin may have a biological effect. However, a causal link between Hh pathway deregulation, Wnt ligand overexpression, nuclear beta-catenin accumulation and increased proliferation remains to be confirmed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Biomarkers, Tumor / analysis*
  • Cadherins / analysis
  • Carcinoma, Basal Cell / chemistry*
  • Carcinoma, Basal Cell / genetics
  • Carcinoma, Basal Cell / pathology
  • Cell Division
  • Cell Nucleus / chemistry*
  • Chi-Square Distribution
  • Cyclin D1 / genetics
  • Cytoskeletal Proteins / analysis*
  • Cytoskeletal Proteins / genetics
  • Female
  • Gene Expression
  • Genes, myc
  • Humans
  • Immunohistochemistry / methods
  • Male
  • Middle Aged
  • Proto-Oncogene Proteins / analysis
  • RNA, Messenger / analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Skin Neoplasms / chemistry*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / pathology
  • Trans-Activators / analysis*
  • Trans-Activators / genetics
  • Wnt Proteins
  • Wnt-5a Protein
  • beta Catenin

Substances

  • Biomarkers, Tumor
  • CTNNB1 protein, human
  • Cadherins
  • Cytoskeletal Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Trans-Activators
  • WNT5A protein, human
  • Wnt Proteins
  • Wnt-5a Protein
  • beta Catenin
  • Cyclin D1