Analysis of β-catenin mutations and α-, β-, and γ-catenin expression in normal and neoplastic human pituitary tissues

The cadherin-catenin system mediates Ca2+-dependent cell-cell adhesion, and genetic alterations in these molecules play a significant role in multistage carcinogenesis. Mutations in the beta -catenin gene, mostly affecting exon 3, have been detected in malignant cell lines and in primary tumors. Immunohistochemical abnormalities in alpha-, beta-, and gamma -catenin have been reported in malignant and benign tumors, and nuclear localization of beta -catenin has been associated with mutations in exon 3 of this gene. Mutational analysis of exon 3 of the beta -catenin gene was undertaken by polymerase chain reaction (PCR) and sequencing using genomic DNA extracted from frozen tissues, including 4 normal pituitaries, 22 pituitary adenomas, and one pituitary carcinoma. Frozen sections from these cases were used for immunohistochemical detection of beta -catenin. We also analyzed immunohistochemical expression of alpha-, beta-, and gamma -catenin by paraffin sections from 154 pituitary tumors, including 148 adenomas and 6 carcinomas. Genomic DNA was extracted from paraffin sections of 2 gonadotroph tumors showing nuclear staining for beta -catenin and was used for PCR and sequencing of exon 3 of the beta -catenin gene. No mutations in exon 3 of the beta -catenin gene were found in any of the 23 cases analyzed by PCR and sequencing. In addition, the 2 cases studied by paraffin section immunohistochemistry, with nuclear staining for beta -catenin, were negative for mutations in this exon. Normal pituitary expressed all three catenin proteins. Immunostaining usually showed a membranous pattern of reactivity and was generally stronger in normal pituitary than in the adjacent adenomas. Stains for alpha -catenin were positive in fewer tumors than for beta -catenin. The lowest frequency immunopositive tumors and the weakest immunostaining was for gamma -catenin. All medically treated prolactinomas were negative for gamma -catenin, whereas treated growth hormone adenomas were less often positive for both alpha- and gamma -catenin than for untreated tumors. The percentage of positive cases for beta -catenin was the same in these two groups. Most pituitary carcinomas were negative for both alpha- and gamma -catenin but were beta -catenin positive. These results indicate that (i) mutations in exon 3 of the beta -catenin gene are uncommon in pituitary tumors, and (ii) expression of alpha-, beta-, and gamma -catenin is decreased in pituitary adenomas compared to normal pituitary tissues.