DELAY OF DIMETHYLBENZ[A]ANTHRACENE-INDUCED MAMMARY TUMORIGENESIS IN TRANSGENIC MICE BY APOPTOSIS INDUCED BY AN UNUSUAL MUTANT P53 PROTEIN

Murine p53 containing an Arg --> Leu substitution at amino acid 172 po ssesses many properties characteristic of wild-type p53, including the ability to induce p21/WAF/Cip1 and apoptosis. To determine if p53-dep endent apoptosis plays a critical role in mammary tumorigenesis, trans genic mice were generated in which the expression of this mutant p53 p rotein was targeted to the mammary gland by using the rat whey acidic protein gene promoter. Mice bearing pituitary isografts were treated w ith 7,12-dimethylbenz[a]anthracene (DMBA) and examined for mammary tum or development. Mice overexpressing the p53 transgene exhibited a stat istically significant increase in apoptosis in the mammary gland and a statistically significant decrease in the incidence of DMBA-induced m ammary tumors. No difference in tumor incidence was observed in mice w ithout pituitary isografts who were treated with DMBA, because the tra nsgene is not overexpressed in the absence of hormone stimulation prov ided by the pituitary isograft. The unexpected wild-type properties of the 172(Arg --> Leu) mutant p53, including its ability to stimulate a poptosis, make it a possible candidate for use in gene therapy protoco ls. (C) 1995 Wiley-Liss, Inc.