PREFERENTIAL OVEREXPRESSION OF A 172(ARG-]LEU) MUTANT P53 IN THE MAMMARY-GLAND OF TRANSGENIC MICE RESULTS IN ALTERED LOBULOALVEOLAR DEVELOPMENT

Regulatory sequences derived from the rat whey acidic protein gene hav e been used to preferentially overexpress a murine 172(Arg-->Leu) muta nt p53 in the mammary gland of transgenic mite. Several different line s of mice expressing the 172(Arg-->Leu) mutant p53 displayed an impair ed ability to lactate, and the mice expressing the highest levels of m utant p53 were unable to nurse their young. This failure was related t o the inhibition of normal lobuloalveolar development that occurred du ring late pregnancy and a marked decrease in milk protein gene express ion at early lactation. Interestingly, immunohistochemical analysis re vealed that the mutant p53 was localized predominantly in the cytoplas m of alveolar tells. Ductal development was not overtly impaired in th ese mice. Expression of the 172(Arg-->Leu) mutant p53 resulted in radi ation-induced apoptosis, and transactivation or repression of the expr ession of a number of genes, including mdm-2 and proliferating cell nu clear antigen, known properties of wild-type p53. The availability of lines of mice preferentially expressing specific p53 mutants in the ma mmary gland should facilitate evaluation of the roles of other factors , such as hormones, oncogenes and chemical carcinogens, in the etiolog y of breast cancer.