INCREASED TUMOR PROLIFERATION AND GENOMIC INSTABILITY WITHOUT DECREASED APOPTOSIS IN MMTV-RAS MICE DEFICIENT IN P53

We have used an in vivo tumor model to evaluate the consequences of p5 3 tumor suppressor protein deficiency in a tissue-specific context. By breeding MMTV-ras transgenic mice, which are highly susceptible to th e development of mammary and salivary tumors, with p53(-/-) mice, we g enerated three classes of animals which contained the MMTV-ras transge ne but differed in their p53 functional status (ras/p(53+/+),ras/p53(/-), or ras/p53(-/-)). ras/p53(-/-) mice developed tumors more rapidly than animals of the other two genotypes; however, the distribution of tumors was unexpectedly altered. Whereas the most frequently observed tumors in ras/p53(+/+) and raslp53+l- mice were of mammary origin, ra sip53-/- mice developed primarily salivary tumors. In addition, the ma mmary and salivary tumors from ras/p53(-/-) mice consistently exhibite d a number of unfavorable characteristics, including higher histologic grades, increased growth rates, and extensive genomic instability and heterogeneity, relative to tumors from ras/p53(+/+) mice. Interesting ly, the increased growth rates of ras/p53(-/-) tumors appear to be due to impaired cell cycle regulation rather than decreased apoptosis, su ggesting that p53-mediated tumor suppression can occur independent of its role in apoptosis.