Translational Significance of p53 Loss of Heterozygosity in Breast Cancer
Abstract
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 (H/+;ErbB2) tumors might be transcriptionally competent towards a subset of targets (p21, Mdm2) and/or 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 G2/M 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 (NIMA)Related 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 G2/M checkpoint after irradiation leading to increased proliferation, chromosomal aberration, selection the cells with p53LOH, ultimately, leading to tumor progression.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2019
- Accession Number
- AD1088154
Entities
People
- Natalia Marchenko
Organizations
- Stony Brook University