Transgenic mouse models in carcinogenesis research and testing

Abstract

Double transgenic mice bearing fusion genes consisting of mouse albumin enhancer/promoter-mouse c- myc cDNA and mouse metallothionein 1 promoter-human TGF-α cDNA were generated to investigate the interaction of these genes in hepatic oncogenesis and to provide a general paradigm for characterizing both the interaction of nuclear oncogenes and growth factors in tumorigenesis. In addition, these mice provide an experimental model to test how environmental chemicals might interact with the c- myc and TGF-α transgenes during the neoplastic process. We show experimental evidence that co-expression of TGF-α and c- myc transgenes in mouse liver promotes overproduction of ROS and thus creates an oxidative stress environment. This phenomenon may account for the massive DNA damage and acceleration of hepatocarcinogenesis observed in the TGF-α/c- myc mouse model. Also, the role of mutagenesis in hepatocarcinogenesis induced by 2-amino-3,8-dimethylimidazo(4,5- f)-quinoxaline (MeIQx) was demonstrated in C57BL/lacZ (Muta™ Mice) and double transgenic c- myc/lacZ mice that carry the lacZ mutation reporter gene. The MeLQx hepatocarcinogenicity was associated with an increase in in vivo mutagenicity as scored by mutations in the lacZ reporter gene. These results suggest that transgenic mouse models may provide important tools for testing both the carcinogenic potential of environmental chemicals and the interaction/cooperation of these compounds with specific genes during the neoplastic process.