Mice Expressing a Mammary Gland–Specific R270H Mutation in the p53 Tumor Suppressor Gene Mimic Human Breast Cancer Development

Abstract

The tumor suppressor gene p53 has an apparent role in breast tumor development in humans, as f30% of sporadic tumors acquire p53 mutations and Li-Fraumeni syndrome patients carrying germ line p53 mutations frequently develop breast tumors at early age. In the present study, conditional expression of a targeted mutation is used to analyze the role of the human R273H tumor-associated hotspot mutation in p53 in mammary gland tumorigenesis. Heterozygous p53 R270H/+ WAPCre mice (with mammary gland-specific expression of the p53.R270H mutation, equivalent to human R273H, at physiologic levels) develop mammary tumors at high frequency, indicating that the R270H mutation predisposes for mammary gland tumor development and acts in a dominant-negative manner in early stages of tumorigenesis. Spontaneous tumor development in these mice is further accelerated by 7,12-dimethylbenz(a)anthracene (DMBA) treatment at young age. The majority of spontaneous and DMBA-induced carcinomas and sarcomas from p53 R270H/+ WAPCre mice is estrogen receptor A positive, and expression profiles of genes also implicated in human breast cancer appear similarly altered. As such, p53 R270H/+ WAPCre mice provide a well-suited model system to study the role of p53 in breast tumorigenesis and the responsiveness of mammary gland tumors to chemotherapeutics. (Cancer Res 2005; 65(18): 8166-73)

Neonatal Experiences Differentially Influence Mammary Gland Morphology, Estrogen Receptor α Protein Levels, and Carcinogenesis in BALB/c Mice

“…It is possible that disruption of p53 protein expression might not be an early step in tumor initiation in this model, although some sort of interference with p53 function may be a necessary step for eventual tumor promotion (as this is a commonly observed event in tumorigenesis; refs. 21,41). Expression of p53 protein in all tissues is typically low, with an increase observed in response to cellular stress or damage (41).…”

“…At the developmental stages of puberty [postnatal day (PND) 30] and young adulthood (PND 60), mammary glands from mice reared in each of these environmental conditions were examined for mRNA and protein levels of both estrogen receptor α (ERα) and tumor-suppressor p53. These factors were chosen as they are considered to play important roles in normal and malignant mammary gland growth (16,21,22). Changes in the molecular profiles of mammary epithelial cells may influence the morphology of the mammary gland, which can also be used to infer cancer risk.…”

Chapter 4 A Mouse Mammary Epithelial Cell Model to Identify Molecular Mechanisms Regulating Breast Cancer Progression

“…There is also difficulty in controlling the level of oncogene overexpression, which is often activated constitutively throughout development, not likely representing the physiologic situation in human breast cancer. The third, and most recent, generation of mouse breast cancer models involves mammary gland-specific gene deletion and activation by use of technology such as the Cre-lox system and tetracycline-responsive transactivation to induce tissue-specific gene mutations in adult somatic tissue and, as such, provides the opportunity to more authentically model human cancer (Furth, 1997;Liu et al, 2007;Moody et al, 2002;Wijnhoven et al, 2005).…”

Genotoxic exposure: novel cause of selection for a functional ΔN-p53 isoform

“…The targeting vectors (Figure 3 and Supplementary Figure 1) were constructed by cloning the mutated fragment into flanking genomic p53 fragments comprising intron 4-3 0 end of the gene (Wijnhoven et al, 2005) together with the transcriptional stop cassette described by Olive et al (2004). This stop cassette contains a puromycin selection marker flanked by LoxP sites.…”

“…Several isoforms of p53 have been identified (Courtois et al, 2002;Candeias et al, 2006;Grover et al, 2009;Marcel and Hainaut, 2009), and point mutations influencing the functionality of p53 were elucidated and mimicked in vivo (de Vries et al, 2002;Wijnhoven et al, 2005;Hoogervorst et al, 2005a;Iwakuma and Lozano, 2007;Heinlein et al, 2008). The p53 gene is the most frequently mutated gene in cancer and analysis of many different human tumor types have shown a high prevalence of missense mutations located primarily in the central DNA-binding domain (Levine, 1997).…”