Effects of genetic background on tumorigenesis in p53‐deficient mice

Abstract

Mice with disrupted germline p53 alleles have been engineered by us and others and have been shown to have enhanced susceptibility to spontaneous tumors of various types. We monitored a large number of p53-deficient mice (p53+/- and p53-/-) and their wild-type littermates (p53+/+) of two different genetic backgrounds (129/Sv and mixed C57BL/6 x 129/Sv) up to 2 yr of age. p53+/- and p53-/- 129/Sv mice show accelerated tumorigenesis rates compared with their p53-deficient counterparts of mixed C57BL/6 x 129/Sv genetic background. The tumor spectra of the two strains of mice are similar except that almost half of 129/Sv p53-/- males develop malignant teratomas, whereas these tumors are rarely observed in C57BL/6 x 129/Sv mice and never in 129/Sv p53+/- males. In the study reported here, we further characterized the lymphomas that arose in the p53-nullizygous mice and found that over three-quarters of the lymphomas were of thymic origin and contained primarily immature (CD4+/CD8+) T-cells, whereas the remainder originated in the spleen and peripheral lymph nodes and were of B-cell type. The high incidence of early-onset lymphomas in the nullizygous mice makes these animals a good lymphoma model, whereas the heterozygous mice may be a useful model for Li-Fraumeni syndrome, a human inherited cancer predisposition.

P53 levels determine outcome during β-catenin tumor initiation and metastasis in the mammary gland and male germ cells

“…The other 10 animals developed an array of tumors typical in P53 þ /À animals around 12 months of age, including rhabdomyosarcomas, osteosarcomas, and lymphomas. (Donehower et al, 1992(Donehower et al, , 1995b. The mammary tumors that did develop in the Tg DNbCat / þ , P53þ /À virgin cohort tended to be similar to the Tg DN-bCat / þ , P53 þ / þ tumors (Figure 1a and b) and contained mainly microacinar structures with regions of disorganized tissue and some invasiveness (data not shown).…”

“…Loss of P53 is associated with dramatic genomic instability and as a result increased mutational events in tumors (Donehower et al, 1995b;Venkatachalam et al, 1998). Given the long latency of tumor initiation in our stochastic MMTV-DNb-catenin mice, we expect that secondary mutation is essential for tumorigenesis in this model.…”

“…Therefore, p53 was an excellent candidate for this mutation. It is surprising that LOH at the wild-type P53 allele was observed in only one of 21 tumors because the single copy of P53 is sufficient to maintain genomic integrity (Donehower et al, 1995b;Venkatachalam et al, 1998). Interestingly, in the case of b-catenin-induced tumors, LOH occurs less frequently (only 4.5% of tumors) than in MMTV-Wnt1, P53 þ /À mice (50% of tumors) or Wnt1 inducible, P53 þ /À mice (19% of tumors) (Donehower et al, 1995a;Gunther et al, 2003).…”

Stochastic modelling of tumorigenesis in p53 deficient mice

“…A trend to tumour multiplicity has also been seen in the p53-deficient mice, but this is of modest extent. From several reports Hursting et al, 1994;Jacks et al, 1994;Kemp et al, 1994;Purdie et al, 1994;Donehower et al, 1995), tumours are almost always single in wild-type mice, multiple tumours (typically no more than two) are occasionally seen in p53+/-mice and two to four tumours are not uncommon in p53-/-mice, although lymphomas in particular may be reported as 'generalized'; for example Hursting et al (1994) recently reported a total of 67 tumours in 52 pS3-/-mice over a 48-week period, with more than one tumour observed in 35% of all tumour-bearing mice. However, tumour multiplicity always remains in single figures and the median number of distinct tumours at presentation is one for all genotypes.…”

“…This allows the number of stages to become a controlled variable in tumorigenesis experiments, a possibility which did not exist until recently. Donehower et al (1995 Experimental data are now available on the time of tumours developing spontaneously in wild-type and p53-deficient mice. The tumours are of several types, but the majority (in all genotypes) are lymphomas, with sarcomas the next most frequent category.…”