Translational Significance of p53 Loss of Heterozygosity in Breast Cancer
[Technical Report, Final Report]
STATE UNIV OF NEW YORK AT STONY BROOK
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Mutations in one allele of the TP53 gene in early stages are frequently followed by the loss of the remaining wild-type p53 wtp53 allele p53LOH during tumor progression. Despite the strong notion of p53LOH as a critical step in tumor progression, its oncogenic outcomes that facilitate the selective pressure for p53LOH occurrence were not elucidated. Using MMTVErbB2 mouse model of breast cancer carrying heterozygous R172H p53 mutation, we identified a novel gain-of-function GOF activity of mutant p53 mutp53 the exacerbated loss of wtp53 allele in response to gamma-irradiation. We show that wild-type p53 allele is partially transcriptionally competent and enables the maintenance of the genomic integrity under normal conditions in mutp53 heterozygous cells. In heterozygous cells gamma-irradiation promotes mutp53 stabilization, which suppresses DNA repair and the cell cycle checkpoint allowing cell cycle progression in the presence of inefficiently repaired DNA, consequently increasing genomic instability leading to p53LOH. Hence, in mutp53 heterozygous cells, irradiation facilitates the selective pressure for p53LOH that enhances cancer cell fitness and provides the genetic plasticity for acquiring metastatic properties. As consequences of p53LOH in mutp53 heterozygous cells, we observed profound stabilization of mutp53 protein, the loss of p21 expression, upregulation of mTOR pathway, the abrogation of G2M checkpoint, chromosomal instability, centrosome amplification, and transcriptional upregulation of mitotic kinase Nek2 involved in the regulation of centrosome function. To avoid the mitotic catastrophe in the absence of G2M checkpoint, cells with centrosome amplification adapt Nek2-mediated centrosomes clustering as pro-survival mutp53 GOF mechanism enabling unrestricted proliferation and clonal expansion of cells with p53LOH. Thus, the clonal dominance of mutp53 cells with p53LOH may represent the mechanism of irradiation-induced p53LOH.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research