Low-dose but not high-dose γ-irradiation elicits the dominant-negative effect of mutant p53 in vivo

Contrary to high doses irradiation (HDR), the biological consequences of dose irradiation (LDR) in breast cancer remain unclear due to the complexity of human epidemiological studies. LDR induces DNA damage that activates p53-mediated tumor-suppressing pathways promoting DNA repair, cell death, and growth arrest. Monoallelic p53 mutations are one of the earliest and the most frequent genetic events in many subtypes of cancer including ErbB2 breast cancer. Using MMTV/ErbB2 mutant p53 (R172H) heterozygous mouse model we found differential p53 genotype-specific effect of LDR vs. HDR on mammary tumorigenesis. Following LDR, mutant p53 heterozygous tumor cells exhibit aberrant ATM/DNA-PK signaling with defects in sensing of double-strand DNA brakes and deficient DNA repair. In contrast, HDR-induced genotoxic stress is sufficient to reach the threshold of DNA damage that is necessary for wtp53 induced DNA repair and cell cycle arrest. As a result, mutant p53 endows dominant-negative effect promoting mammary tumorigenesis after low-impact DNA damage leading to the selection of a genetically unstable proliferative population, with negligible mutagenic effect on tumors carrying wtp53 allele.