β-catenin nuclear accumulation in head and neck mucoepidermoid carcinoma: Its role in cyclin D1 overexpression and tumor progression

Background. Nuclear/cytoplasmic accumulation of β-catenin is mainly regulated by its degradation, which is initiated by interaction with adenomatous polyposis coli (APC) protein. Accumulation of β-catenin activates the transcription of 1 of the target oncogenic genes, cyclin D1, in the Wnt/Wingless pathway. The role of β-catenin and cyclin D1 in this pathway has not been previously studied in head and neck mucoepidermoid carcinoma (MEC). This study investigates abnormalities of β-catenin and the APC gene in MEC and correlates the patterns of cyclin D1 overexpression and nuclear/cytoplasmic accumulation of β-catenin with the clinical outcome. Methods. Mutations of the β-catenin and APC genes, as well as overexpression of cyclin D1, were investigated by polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) in tissue samples from 44 cases of MEC. In addition, we employed differential PCR method to detect amplification of the cyclin D1 gene. Furthermore, the overexpression of cyclin D1 and nuclear/cytoplasmic accumulation of β-catenin was examined by immunohistochemistry, and any correlation with clinicopathologic parameters was evaluated. Results. Nuclear/cytoplasmic accumulation of β-catenin was observed in 6 of 44 MEC cases (13.6%), 5 of which were high-grade MEC, while the other 1 case was intermediate-grade tumor. Mutational analysis of exon 3 of the β-catenin gene revealed that 4 of 26 cases (15.4%) contained point mutations (3 in codon 32, GAC [Asp] to GGC [Gly]; 1 in codon 42, ACA [Thr] to ATA [Ile]), and all these 4 cases showed β-catenin accumulation immunohistochemically. The nuclear/cytoplasmic accumulation of β-catenin was significantly correlated with the adverse outcome of patients (p = .011). Two APC gene alterations were detected in 2 cases of low-grade MEC, where there was no β-catenin nuclear accumulation. Amplification of the cyclin D1 gene was observed in 10 of 26 cases (38.5%). Cyclin D1 overexpression was recognized in 19 of 44 cases (43.2%) and was significantly correlated with β-catenin accumulation (p = .003). Conclusions. These findings suggest that β-catenin, which, in cooperation with cyclin D1, plays crucial role in the Wnt-signaling pathway, may also contribute to the adverse outcome and high-grade tumor staging of MEC.