Development of Spontaneous Mammary Tumors in BALB/c p53 Heterozygous Mice

Abstract

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.

Phosphorylation of Ser312 contributes to tumor suppression by p53 in vivo

“…This strongly indicates that the mutation of p53, rather than the genetic background, sensitizes these mice to tumor development. The influence of strain on tumor outcome is well documented; e.g., p53-null mice develop teratocarcinomas in a 129/Sv background, whereas p53 +/− BALB/c mice are susceptible to mammary tumors (29,30). Subtle variations may exist between mouse strains in pathways modulated by irradiation that may influence tumor outcome.…”

The emerging role of p53 in stem cells

“…Accordingly, p53 À/À mice, at least in the murine genetic background C57/BL6, rarely develop mammary tumors [34,[36][37][38][39]. Nevertheless, several observations suggest that loss of p53 is involved in the etiopathology of both human and mouse mammary tumors: (i) mutations of p53 are found in many breast cancers and women affected by the Li-Fraumeni syndrome (an inherited predisposition to cancer development linked to germline mutations in the p53 gene) often develop breast tumors [38]; (ii) in the BALB/c background, approximately 75% of p53 À/À mice have microscopic lesions in the mammary gland (sarcomas, epithelial hyperplasia and alterations in stromal morphology) [40]; (iii) transplantation of the p53 À/À BALB/c epithelium into fat pads of WT syngeneic mice leads to the development of mammary carcinomas in 60-75% of mice [40,41]; (iv) in a conditional mammary tumor model, approximately 70% of mice that carry tissue-specific inactivation of p53 develop mammary carcinomas [42]; and (v) in ErbB2 transgenic mice, which develop mammary carcinomas with high penetrance and short latency, p53 impairment is responsible for the immortal behavior and the geometric expansion of mammary CSCs in vitro and for carcinoma growth in vivo [34].…”

Estrogen receptor-positive mammary tumorigenesis in TGFα transgenic mice progresses with progesterone receptor loss

“…Cystic papillary tumors in NRL-TGFa mice resemble those of other TGFa transgenic mice (Humphreys and Hennighausen, 2000;Rose-Hellekant and Sandgren, 2000;Arendt et al, 2006). Concurrent expression of heterozygous p53 results in aggressive solid tumors of varying types reflecting the tumor spectrum of p53 þ /À BALB/c mice (Blackburn et al, 2003;Jerry et al, 2000;Kuperwasser et al, 2000), although relative proportions cannot be determined due to low numbers of p53 þ /À mice in the present study. The B6 background delayed tumor latency in NRL-TGFa mice, similar to that observed previously in WAP-TGFa mice (RoseHellekant et al, 2002) and p53 þ /À (BALB/c:B6) F1 mice (Jerry et al, 2000), suggesting that B6 alleles protect against mammary cancer.…”