Development of spontaneous mammary tumors in BALB/c p53 heterozygous mice. A model for Li-Fraumeni syndrome.
Breast cancer is the most frequent tumor type among women in the United States and in individuals with Li-Fraumeni syndrome. The p53 tumor suppressor gene is altered in a large proportion of both spontaneous breast malignancies and Li-Fraumeni breast cancers. This suggests that loss of p53 can accelerate breast tumorigenesis, yet p53-deficient mice rarely develop mammary tumors. To evaluate the effect of p53 loss on mammary tumor formation, the p53(null) allele was back-crossed onto the BALB/c genetic background. Median survival was 15.4 weeks for BALB/c-p53(-/-) mice compared to 54 weeks for BALB/c-p53(+/-) mice. Sarcomas and lymphomas were the most frequent tumor types in BALB/c-p53(-/-) mice, whereas 55% of the female BALB/c-p53(+/-) mice developed mammary carcinomas. The mammary tumors were highly aneuploid, frequently lost the remaining wild-type p53 allele, but rarely lost BRCA1. Although mammary tumors were rarely detected in BALB/c-p53(-/-) female mice, when glands from BALB/c-p53(-/-) mice were transplanted into wild-type BALB/c hosts, 75% developed mammary tumors. The high rate of mammary tumor development in the BALB/c background, but not C57Bl/6 or 129/Sv, suggests a genetic predisposition toward mammary tumorigenesis. Therefore, the BALB/c-p53(+/-) mice provide a unique model for the study of breast cancer in Li-Fraumeni syndrome. These results demonstrate the critical role that the p53 tumor suppressor gene plays in preventing tumorigenesis in the mammary gland.
Kuperwasser
C
C
Program in Molecular and Cellular Biology, Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, Massachusetts, USA.
Hurlbut
G D
GD
Kittrell
F S
FS
Dickinson
E S
ES
Laucirica
R
R
Medina
D
D
Naber
S P
SP
Jerry
D J
DJ
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D019398:Genes, BRCA1 / Q000235:genetics; D006579:Heterozygote; D015994:Incidence; D016864:Li-Fraumeni Syndrome / Q000235:genetics*; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C / Q000235:genetics*; D008815:Mice, Inbred Strains; D010641:Phenotype; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics*
D016159:Tumor Suppressor Protein p53