A mammary-specific model demonstrates the role of the p53 tumor suppressor gene in tumor development

Abstract

Although alterations in the p53 tumor suppressor gene are detected frequently in human breast cancers, mammary tumors are observed infrequently in p53 null mice. This has led to the suggestion that absence of p53 alone is not sucient for induction of mammary tumors. However, early death of p53 null mice from thymic lymphomas may obscure tumor phenotypes that would develop later. Therefore, p53null mammary epithelium was transplanted into cleared mammary fat pads of wild type p53 BALB/c hosts to allow long-term analysis of mammary tumor phenotypes. Five treatments were compared for their eects on tumor incidence in hosts bearing transplants of p53 null vs p53 wt mammary transplants for each treatment group were 62% vs 0%, 100% vs 0%, 68% vs 0%, 60% vs 4% and 91% vs 14%, respectively. The mammary tumors that developed in the p53 null mammary epithelium were all adenocarcinomas and were frequently aneuploid. These data demonstrate that the absence of p53 is sucient to cause development of mammary tumors and that hormonal stimulation enhances the tumorigenicity of p53 null mammary epithelium to a greater extent than DMBA exposure alone. This model provides an in situ approach to examine the molecular basis for the role of p53 in the regulation of mammary tumorigenesis.

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.…”

“…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. The increased incidence, shortened latency and increased tumor grade conferred by p53 heterozygosity in the NRL-TGFa model is similar to other transgenic mice expressing mammary oncogenes concurrently with heterozygous, null or mutated p53 (e.g.…”

Ovarian hyperstimulation induces centrosome amplification and aneuploid mammary tumors independently of alterations in p53 in a transgenic mouse model of breast cancer

“…p53-null MECs transplanted into the mammary gland fat pads of wildtype mice develop spontaneous tumors with high penetrance . An increase in tumor formation was observed in the presence of hormonal stimulation with pituitary isografts, resulting in adenocarcinomas with varying composition of aneuploid cells (Jerry et al, 2000). These data suggest that hormonal stimulation contributes to the acquisition of aneuploidy in a p53-deficient environment.…”