A gain of function p53 mutant promotes both genomic instability and cell survival in a novel p53-null mammary epithelial cell model

Approximately 40% of human breast cancers contain alterations in the tumor suppressor p53, The p53 172R-H gain-of-function mutant (equivalent to the c ommon 175R-H human breast cancer mutant) has been shown to promote aneuploi dy and tumorigenesis in the mammary gland in transgenic mice and may affect genomic stability in part by causing centrosome abnormalities, The precise mechanism of action of these gain-of-function mutants is not well understo od, and has been studied primarily in fibroblast cell lines. A novel p53-nu ll mouse mammary epithelial cell line developed from p53-null mice has been used in adenovirus-mediated transient transfection experiments to study th e properties of this p53 mutant, Marked centrosome amplification and an inc reased frequency of aberrant mitoses were observed within 72 h of introduct ion of p53 172R-H. However, few cells with aberrant centrosome numbers were observed in cells stably expressing the p53 172R-H mutant. Furthermore, st able expression of this p53 mutant reduced both basal and DNA damage-induce d apoptosis, This result may be mediated in part through abrogation of p73 function. The p53 172R-H mutant, therefore, appears to influence tumorigene sis at the molecular level in two distinct ways: promoting the development of aneuploidy in cells while also altering their apoptotic response after D NA damage,-Murpby, K. L., Dennis, A. P., Rosen, J. M. A gain of function p5 3 mutant promotes both genomic instability and cell survival in a novel p53 -null mammary epithelial cell model.