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Alterations of ß- and -Catenin in N-Butyl-N-(-4-hydroxybutyl)nitrosamine-induced Murine Bladder Cancer¹

Departments of Urology and Biochemistry, Shimane Medical University, Izumo, 693-0085 Japan [H. S., M. I., S. U., K. S., T. Y., M. T.], and Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, California 94121 [M. D., L. R-F., R. D.]

Abnormal degradation of ß-catenin caused by alteration of the glycogen synthase kinase-3ß (GSK-3ß) consensus motif is an important step for carcinogenesis. We hypothesize that ß- and -catenin may play an important role in the pathogenesis of bladder cancer. We tested this hypothesis through analysis of ß- and -catenin in both murine and human bladder cancers. A murine bladder cancer model was prepared by use of N-butyl-N-(-4-hydroxybutyl)nitrosamine (BBN) in 6-week-old male B6D2F1 mice. After 4, 8, 12, 16, 20, 24, and 28 weeks of BBN treatment, bladder specimens were harvested and analyzed for both protein and gene expression for ß- and -catenin. Mutational analysis of the NH₂-terminal regulatory domains of ß- and -catenin was performed in each specimen by PCR-single-strand conformational polymorphism (SSCP) analysis. Mutations were further confirmed by direct DNA sequencing with a dye terminator method. Human bladder cancer specimens with normal tissues, dysplasia, carcinoma in situ, and carcinoma of grades, 1, 2, and 3 were also analyzed for ß- and -catenin expression. ß- and -catenin were analyzed for mutations by SSCP and direct DNA sequencing. Intracellular accumulation of ß- and -catenin was observed in 6 of 20 invasive carcinoma specimens. There was no intracellular accumulation of ß- and -catenin in mucosal dysplasia, papillary or nodular dysplasia, and carcinoma in situ specimens. On an SSCP analysis for ß-catenin, abnormal bandshifts were detected in two invasive carcinomas with intracellular ß-catenin accumulation. Further sequencing revealed two mutations [AGT(S) to ATT(I) and TCT(S) to CCT(P)] within the consensus motif for GSK-3ß phosphorylation. On the other hand, SSCP analysis for -catenin followed by sequencing revealed three mutations in two invasive carcinomas with intracellular accumulation of -catenin. These three alterations affected the 3' downstream region outside the GSK-3ß phosphorylation site [ACC(T) to GCC(A), CTC(L) to ATC(I), and CTC(L) to ATG(M)]. In human bladder cancer, ß- and -catenin expression was significantly weaker than in normal bladder. On SSCP analysis one abnormal bandshift was observed in high-grade human bladder cancer with intracellular ß-catenin accumulation. DNA sequencing revealed mutation TCT(S) to TGT(C). In summary, alterations in ß- and -catenin are late events favoring tumor progression in mouse BBN-induced bladder cancer. Changes affecting the GSK-3ß phosphorylation site appear to be associated with activation of ß-catenin, but not with activation of -catenin. In human blabber cancer, ß- and -catenin expression is similar to the expression in the mouse model. The present study demonstrates that ß- and -catenin may play an important role in bladder cancer progression.

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