Reduced p53 dosage associated with mammary tumor metastases in C3(1)/TAG transgenic mice.
Transgenic mice expressing the simian virus 40 large T-antigen (TAG) under the regulatory control of the rat prostatic steroid binding protein C3(1) gene develop mammary carcinomas (in females) and prostate carcinomas (in males). The development of carcinomas occurs several months after the appearance of dysplastic lesions, suggesting that TAG is necessary but insufficient for tumor formation and that other genetic events are involved in this process. TAG is known to bind to p53 and to result in its functional inactivation, which is believed to be a critical step in TAG-induced transformation. We investigated whether the TAG-p53 interaction is rate limiting in the development of phenotypic changes in these transgenic mice by crossing C3(1)/TAG transgenics with mice carrying null mutations of the p53 gene. TAG-expressing animals with a p53+/- genotype developed much more aggressive mammary tumors, as evidenced by increased numbers and size of metastases, than did TAG-expressing animals carrying two wild-type p53 alleles. While p53 was expressed in primary tumors, p53 expression appeared to be reduced or lost in many metastases in mice carrying either the p53+/+ or p53+/- genotypes. The tumorigenic process did not appear to be due to the loss of the second wild-type p53 allele or the gain of dominant oncogenic mutations in p53, as no mutations were detected in either primary or metastatic tumors by polymerase chain reaction--single-strand conformation polymorphism analyses. These findings suggest that despite the presence of TAG, p53 levels influence the characteristics of the late stages of mammary tumor growth and accelerate metastases. Functional loss of p53 and not p53 mutations participates in TAG-induced mammary carcinoma development and progression.
Maroulakou
I G
IG
Laboratory of Chemoprevention, National Cancer Institute, Bethesda, MD 20892, USA.
Shibata
M A
MA
Jorcyk
C L
CL
Chen
X X
XX
Green
J E
JE
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology*; D000483:Alleles; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000096:biosynthesis / Q000235:genetics; D015152:Blotting, Northern; D002455:Cell Division / Q000502:physiology; D005260:Female; D016158:Genes, p53; D007150:Immunohistochemistry; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology
D000952:Antigens, Polyomavirus Transforming; D016159:Tumor Suppressor Protein p53