P53 heterozygosity leads to deregulated apoptosis and cell proliferation in the mammary gland of ERα over-expressing mice.

Abstract

Abstract Abstract #2008 Background: Transgenic mouse models are a common experimental tool for unraveling gene function. Breast cancer develops as genetic changes accumulate in the ductal epithelium giving rise to precursor lesions such as atypical ductal hyperplasias, which may progress to ductal carcinoma in situ (DCIS) and eventually invasive breast cancer. This process is associated with mutations in tumor suppressor genes such as p53 resulting in the deregulation of essential genes. p53 plays a role in mediating cell response to various stresses by inducing or repressing genes involved in cell cycle arrest, senescence, apoptosis and DNA repair. Studies have shown that p53 is a predictor for local recurrence of DCIS. About 65% of breast cancers are estrogen receptor alpha (ERα) positive and estrogen dependent. Deregulated expression of ERα in normal breast epithelium has been found in conjunction with breast cancer, leading to the concept that loss of the normal regulatory mechanisms that control expression levels of ERα in normal breast epithelium may increase the risk for the development of breast cancer. This study tests the hypothesis that p53 heterozygosity may lead to an aberrant growth response to hormonal stimuli and development of mammary gland preneoplasia.
 Methodology: To examine if p53 heterozygosity promotes disease in mammary glands with deregulated expression of ERα, a conditional ERα in mammary tissue mouse model (MMTV-rtTA/tet-op-ERα or CERM) was bred to a p53 homozygous mutant (p53-/-) mouse model. For progression studies, mammary glands were collected at 12 months of age for morphological and histological studies both in intact nulliparous mice. A group of mice was ovariectomized at 14 weeks of age and 2 weeks later treated with either placebo or 17β-estradiol for 48 hours to dissect the molecular events attributable to specific hormonal stimulation as compared to normal ovarian function.
 Results: Loss of p53 resulted in a statistically significant higher percentage of hyperplastic alveolar nodules, both by itself and in mice with ERα deregulation in the mammary gland. p53 heterozygosity resulted in a higher incidence of morphological and histological abnormalities such as dilated ducts, ductal dysplasia, ductal carcinoma in situ, and abnormal stroma. These lesions showed higher rates of cell proliferation and lower rates of apoptosis. Phospho-p53 immunohistochemistry showed evidence of DNA damage in the p53 heterozygous mice. There was no significant change in the terminal ductal structures in mammary glands of ovariectomized mice when compared to mice treated with exogenous 17β-estradiol after 48 hrs.
 Conclusions: p53 heterozygosity predisposed mammary tissue to preneoplastic changes both by itself and in collaboration with deregulated ERα expression. The combination of deregulated ERα expression and p53 heterozygosity was associated with more disease than either genetic change by itself. Loss of p53 leads to a deregulation in apoptosis and cell proliferation in the mammary gland of ERα over-expressing mice suggesting that both processes are involved in the development of preneoplasia. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2008.