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


OBJECTIVE
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.
Saldanha
G
G
Department of Cancer Studies and Molecular Medicine, University of Leicester, UK. gss4@le.ac.uk
Ghura
V
V
Potter
L
L
Fletcher
A
A
D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D015820:Cadherins / Q000032:analysis; D002280:Basal Cell Carcinoma / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D002455:Cell Division; D002467:Cell Nucleus / Q000737:chemistry*; D016009:Chi-Square Distribution; D019938:Cyclin D1 / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000032:analysis* / Q000235:genetics; D005260:Female; D015870:Gene Expression; D016259:Genes, myc; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D015534:Trans-Activators / Q000032:analysis* / Q000235:genetics; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051176:beta Catenin
D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051176:beta Catenin; D019938:Cyclin D1