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Translational Significance of p53 Loss of Heterozygosity in Breast Cancer

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Technical Report,01 Sep 2017,31 Aug 2018

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Research Foundation for SUNY Stony Brook 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 1 Using MMTVErbB2 mouse model carrying heterozygous R172H p53 mutation, we show that under normal condition, transcriptionally competent wtp53 allele enables the genomic integrity and suppresses the mTOR pathway in mutp53 heterozygous ErbB2 cancer cells 2 In the long run, the single dose of irradiation of premalignant lesions accelerates mammary tumorigenesis, induces p53LOH and metastases that are more profound in the presence of mutant p53 allele 3 As an early response in mutant p53 heterozygous cells, genotoxic stress promotes sustained mutant p53stabilization, continuous DNA damage, and aberrant G1-S transition 4 Mechanistically, the deficient cell cycle checkpoint coupled within efficiently repaired DNA underlies the higher frequency of p53LOH in mutant p53 heterozygous cells 5 The main physiological outcomes of p53LOH are profound stabilization of mutant p53 protein, mTOR upregulation, enhanced genomic instability, and metastases. Collectively, our results imply that in mutant p53 heterozygous cells, genotoxic stress facilitates the selective pressure for wtp53 loss. The latter enhances cancer cells fitness by mTOR upregulation and provides the genetic plasticity for the acquisition of metastatic properties.

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  • Medicine and Medical Research
  • Medicine and Medical Research

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