Selective inactivation of p53 facilitates mouse epithelial tumor progression without chromosomal instability

We examined the selective pressure for, and the impact of, p53 inactivation during epithelial tumor evolution in a transgenic brain tumor model. In Tg T(121) Mice, cell-specific inactivation of the pRb pathway in brain choroid plexus epithelium initiates tumorigenesis and induces p53-dependent apopto sis. We previously showed that p53 deficiency accelerates tumor growth due to diminished apoptosis. Here we show that in a p53(+/-) background, slow-g rowing dysplastic tissue undergoes clonal progression to solid angiogenic t umors in all animals. p53 is inactivated in all progressed tumors, with los s of the wild-type allele occurring in 90% of tumors. Moreover, similar pro gression occurs in 38% of TgT(121)p53(+/+) mice, also with loss of at least one p53 allele and inactivation of p53. Thus, the selective pressure for p 53 inactivation, likely based on its apoptotic function, is high. Yet, in a ll cases, p53 inactivation correlates with progression beyond apoptosis red uction, from dysplasia to solid vascularized tumors. Hence, p53 suppresses tumor progression in this tissue by multiple mechanisms. Previous studies o f fibroblasts and hematopoietic cells show that p53 deficiency can be assoc iated with chromosomal instability, a mechanism that may drive tumor progre ssion. To determine whether genomic gains or losses are present in tumors t hat progress in the absence of p53, we performed comparative genomic hybrid ization analysis. Surprisingly, the only detectable chromosomal imbalance w as partial or complete loss of chromosome 11, which harbors the p53 gene an d is thus the selected event. Flow cytometry confirmed that the majority of tumor cells were diploid. These studies indicate that loss of p53 function is frequent under natural selective pressures and furthermore that p53 los s can facilitate epithelial tumor progression by a mechanism in addition to apoptosis reduction and distinct from chromosomal instability.