REDUCED P53 DOSAGE ASSOCIATED WITH MAMMARY-TUMOR METASTASES IN C3(1) T-AG TRANSGENIC MICE/

Transgenic mice expressing the simian virus 40 large T-antigen (T-AG) under the regulatory control of the rat prostatic steroid binding prot ein C3(1) gene develop mammary carcinomas (in females) and prostate ca rcinomas (in males). The development of carcinomas occurs several mont hs after the appearance of dysplastic lesions, suggesting that T-AG is necessary but insufficient for tumor formation and that other genetic events are involved in this process. T-AG is known to bind to p53 and to result in its functional inactivation, which is believed to be a c ritical step in T-AG-induced transformation. We investigated whether t he T-AG-p53 interaction is rate limiting in the development of phenoty pic changes in these transgenic mice by crossing C3(1)/T-AG transgenic s with mice carrying null mutations of the p53 gene. T-AG-expressing a nimals with a p53(+/-) genotype developed much more aggressive mammary tumors, as evidenced by increased numbers and size of metastases, tha n did T-AG-expressing animals carrying two wild-type p53 alleles. Whil e p53 was expressed in primary tumors, p53 expression appeared to be r educed or lost in many metastases in mice carrying either the p53(+/+) or p53(+/-) genotypes. The tumorigenic process did not appear to be d ue to the loss of the second wild-type p53 allele or the gain of domin ant oncogenic mutations in p53, as no mutations were detected in eithe r primary or metastatic tumors by polymerase chain reaction-single-str and conformation polymorphism analyses. These findings suggest that de spite the presence of T-AG, p53 levels influence the characteristics o f the late stages of mammary tumor growth and accelerate metastases. F unctional loss of p53 and not p53 mutations participates in T-AG-induc ed mammary carcinoma development and progression. (C) 1997 Wiley-Liss, Inc.