Inactivation of p53 and the development of tetraploidy in the elastase-SV40 T antigen transgenic mouse pancreas.

Human pancreatic cancer develops in association with an acquired genomic instability, but the events that lead to instability are difficult to investigate because they occur sporadically and unpredictably. The elastase-SV40 T antigen transgenic mouse model of pancreatic adenocarcinoma reproducibly proceeds through a diploid --> tetraploid --> multiple aneuploid sequence of genetic abnormalities. We investigated the relationship between inactivation of p53 and development of tetraploidy in this model. Because T antigen inactivates p53 by forming a stable complex with it, we used multiparameter flow cytometry to assess p53 expression in pancreatic samples of transgenic and control mice between 8 and 24 days of age. On day 18, a cell cycle-specific inactivation of p53 developed between diploid G, and S phase and was associated with the appearance of a cycling tetraploid cell population that had p53 protein overexpression in both G1- and S-phase cells. Cytogenetic analysis of pancreatic samples confirmed the development of a tetraploid cell population. Inactivation of p53 in diploid cells of the transgenic pancreas is followed by the development of a tetraploid cell population. We have shown previously that this tetraploid intermediate is predisposed to progression to aneuploidy because it has abnormal mitotic poles. Therefore, our results suggest that inactivation of p53 by T antigen leads to formation of a tetraploid cell intermediate that is predisposed to chromosome segregation abnormalities and the development of multiple aneuploid cell populations.