C-MYC IN BLADDER-CANCER - CLINICAL FINDINGS AND ANALYSIS OF MECHANISM

The c-myc gene product is known to be involved in the regulation of ce ll proliferation and differentiation. Altered c-myc gene expression is a common event in a variety of tumors. This study was designed to inv estigate c-myc overexpression in transitional cell carcinoma (TCC). Th e first part was designed to investigate the frequency of c-myc overex pression in relation to tumor stage and tumor grade. A second set of e xperiments was directed at the mechanisms underlying c-myc overexpress ion in TCC. A total of 185 paraffin-embedded urothelial tissue specime ns were investigated immunohistochemically for c-myc overexpression. A single case of overexpression (6%) was observed in normal urothelial tissue (n = 16). c-myc overexpression was also infrequent in carcinoma in situ (TIS) (7/39 = 18%). In contrast, papillary urothelial tumors (n=65) yielded c-myc overexpression in 38 cases (58%). Investigation o f infiltrating bladder tumors revealed c-myc overexpression in 56% of T1 tumors and 59% of muscle-infiltrating tumors. The staining pattern in multifocal tumors was heterogeneous in 10 of 18 cases. Similarly, o nly 12 of 28 patients with tumor recurrences showed the same c-myc sta ining pattern in the primary tumor and in tumor recurrences. c-myc ove rexpression did not correlate with tumor grade or tumor progression. N evertheless, the high frequency of c-myc overexpression in urothelial carcinoma suggests an important role for this protein in urothelial ca rcinoma. Therefore, the mechanism underlying c-myc overexpression was further investigated in six bladder carcinoma cell lines. Southern blo t experiments under standardized conditions showed no significant gene amplification. The comparison of c-myc mRNA expression to that of his tone H3 as a measure of cell proliferation revealed a moderate correla tion (r = 0.45) in the six cell lines examined. These data suggest tha t in accord with its established role as a cell cycle competence facto r, c-myc may be necessary but not sufficient for the induction of prol iferation in urothelial carcinoma.