Translational Significance of p53 Loss of Heterozygosity in Breast Cancer
Technical Report,01 Sep 2018,31 Aug 2019
Stony Brook University Stony Brook United States
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Mutations in one allele TP53 gene in early stages frequently followed by the loss of the remaining wild-type allele LOH in later stages of tumor development. Despite the strong notion that p53LOH promotes tumorigenesis, its specific role in acute and long-term response to genotoxic modalities remained unclear. The major innovative findings for the reporting period are the following. We established that wtp53 in mutp53 heterozygous HErbB2 tumors might be transcriptionally competent towards a subset of targets p21, Mdm2 andor mutp53 may exert dominant-negative effect and suppress subset of wtp53 targets Gadd45 in response to irradiation. As physiological consequences of p53LOH in vivo and in vitro we found that p53LOH leads to the loss of transcriptional activation of p21 and abrogation of G2M checkpoint 2 stabilization of mutp53 protein 3 aggravation centrosome aberrations leading to increased genomic and chromosomal instability 4 increased cells proliferation 5 transcriptional upregulation of genes involved in mitosis, including Nek2 member of Never in Mitosis NIMARelated Kinases family 6 the increased sensitivity of mutp53 cancer cells to Nek2 inhibition. In the presence of mutp53 allele, the decreased expression of Gadd45 and increased expression of Nek2 may drive cell cycle trough G2M checkpoint after irradiation leading to increased proliferation, chromosomal aberration, selection the cells with p53LOH, ultimately, leading to tumor progression.
- Medicine and Medical Research