Urothelium-specific expression of an oncogene in transgenic. mice induced the formation of carcinoma in situ and invasive transitional cell carcinoma

Although many genetic alterations are known to be associated with human tra nsitional cell carcinoma (TCC) of the urinary bladder, relatively little is known about the roles of these molecular defects, singular or in combinati on, in bladder tumorigenesis. We have developed a transgenic mouse model of bladder tumorigenesis using a 3.6-kb promoter of uroplakin II gene to driv e the urothelium-specific expression of oncogenes, In this study, we demons trate that transgenic mice bearing a low copy number of SV40T transgene dev eloped bladder carcinoma in situ (CIS), whereas those bearing high copies d eveloped CIS as well as invasive and metastatic TCCs. These results indicat e that the SV40T inactivation of p53 and retinoblastoma gene products, defe cts frequently found in human bladder CIS and invasive TCCs, can cause the aggressive form of TCC. Our results also provide experimental proof that CI S is a precursor of invasive TCCs, thus supporting the concept of two disti nct pathways of bladder tumorigenesis (papillary verses CIS/invasive TCC). This transgenic system can be used for the systematic dissection of the rol es of individual or combinations of specific molecular events in bladder tu morigenesis.