Alterations of beta-catenin pathway in non-melanoma skin tumors: loss of alpha-ABC nuclear reactivity correlates with the presence of beta-catenin gene mutation.
To determine the role of beta-catenin pathway in human skin carcinogenesis, 135 non-melanoma skin tumors were analyzed for beta-catenin expression and gene mutations. Intense nucleo-cytoplasmic immunoreactivity for C terminus beta-catenin antibodies was observed in all pilomatricomas and in single cases of trichoepithelioma and squamous cell carcinoma showing peculiar signs of matrical differentiation. Moderate increase of beta-catenin nuclear staining was detected in a significant proportion of basal cell carcinomas, Bowen disease, spiroadenomas, and occasionally also in squamous cell carcinomas, but in these neoplasms only a limited fraction of tumor cells accumulated beta-catenin. Molecular analysis revealed that beta-catenin gene mutations are a peculiar feature of skin tumors with matrical differentiation and correlate with a pattern of intense and diffuse beta-catenin nuclear expression. In contrast, adenomatous polyposis coli (APC) and AXIN2 mutations were not involved in skin tumorigenesis. Analysis of Wnt pathway revealed that TCF-1 and MITF-M were selectively induced in the tumor types harboring beta-catenin mutations, indicating that a Wnt/beta-catenin pathway involving TCF-1 and MITF-M is activated in these tumors. Interestingly, high expression levels of TCF-3 were found in basal cell carcinomas and spiroadenomas. TCF-3 is reported to act as a negative modulator of beta-catenin degradation pathway. Thus, the moderate increase of beta-catenin nuclear staining detected in these tumor types might, at least in part, be due to a TCF-3-dependent mechanism. Finally, we found that the presence of beta-catenin mutations significantly correlated with loss of nuclear immunoreactivity for an antibody raised against the N terminus of beta-catenin (alphaABC). Thus, a combined analysis with C terminus-beta-catenin antibodies and alphaABC Ab may represent a powerful investigative approach for the detection of beta-catenin structural alterations.
Doglioni
Claudio
C
Department of Histopathology, Belluno City Hospital, Belluno, Italy.
Piccinin
Sara
S
Demontis
Silvia
S
Cangi
Maria Giulia
MG
Pecciarini
Lorenza
L
Chiarelli
Concetta
C
Armellin
Michela
M
Vukosavljevic
Tamara
T
Boiocchi
Mauro
M
Maestro
Roberta
R
D000911:Antibodies, Monoclonal; D060466:Axin Protein; D002467:Cell Nucleus / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D004252:DNA Mutational Analysis; D017491:Genes, APC; D006801:Humans; D007150:Immunohistochemistry; D009154:Mutation; D012867:Skin / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D051176:beta Catenin
C491761:AXIN2 protein, human; D000911:Antibodies, Monoclonal; D060466:Axin Protein; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin