To determine the role of β-catenin pathway in human skin carcinogenesis, 135 non-melanoma skin tumors were analyzed for β-catenin expression and gene mutations. Intense nucleo-cytoplasmic immunoreactivity for C terminus β-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 β-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 β-catenin. Molecular analysis revealed that β-catenin gene mutations are a peculiar feature of skin tumors with matrical differentiation and correlate with a pattern of intense and diffuse β-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 β-catenin mutations, indicating that a Wnt/β-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 β-catenin degradation pathway. Thus, the moderate increase of β-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 β-catenin mutations significantly correlated with loss of nuclear immunoreactivity for an antibody raised against the N terminus of β-catenin (αABC). Thus, a combined analysis with C terminus-β-catenin antibodies and αABC Ab may represent a powerful investigative approach for the detection of β-catenin structural alterations.
|Number of pages||11|
|Journal||American Journal of Pathology|
|Publication status||Published - Dec 2003|
ASJC Scopus subject areas
- Pathology and Forensic Medicine