In order to test whether cyclin E-mediated chromosome loss could indeed synergize with tumor suppressor mutations, we utilized a mouse model. Trangenic mice were constructed that were heterozygously mutated at either the Rb orp53 locus and that carried a hormone-responsive cyclin E transgene expressed during pregnancy and lactation in the mammary epithelium. In this instance, an allele of cyclin E refractory to ubiquitin-mediated proteolysis was used to maximally deregulate cyclin E through the cell cycle. Female mice were subjected to two pregnancies, aged, and monitored for mammary tumorigenesis. While the cyclin E transgene and the heterozygous p53 mutation alone each conferred mammary tumorigenesis at a rate of 10% or less, approximately 60% ofmice carrying both thep53 mutation and the cyclin E transgene developed mammary tumors. This strong significant genetic interaction is consistent with the hypothesis that cyclin E-mediated chromosome instability causes increased levels of LOH. Indeed, when tumors were analyzed for p53 gene status, allelic loss had occurred in all cases.
No such interaction was observed between cyclin E deregulation and Rb heterozygosity. However, there is a caveat related to this experiment in that Rb heterozygous mice have a limited lifespan, and must be euthanized at year of age because of a highly penetrant pituitary tumor phenotype. On the other hand, mammary tumorigenesis induced by cyclin E deregulation alone or in concert with p53 heterozygosity usually occurs between 12 and 18 mo. Consequently, a potential interaction between cyclin E deregulation and Rb heterozygosity may have been inaccessible due to experimental design limitations.
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