Genetic modifiers regulating DNA replication and double-strand break repair are associated with differences in mammary tumors in mouse models of Li-Fraumeni syndrome

Abstract

Breast cancer is the most common tumor among women with inherited variants in the TP53 tumor suppressor, but onset varies widely suggesting interactions with genetic or environmental factors. Rodent models haploinsufficent for Trp53 also develop a wide variety of malignancies associated with Li-Fraumeni Syndrome, but BALB/c mice are uniquely susceptible to mammary tumors and is genetically linked to the Suprmam1 locus on chromosome 7. To define mechanisms that interact with deficiencies in p53 to alter susceptibility to mammary tumors, we fine-mapped the Suprmam1 locus in females from an N2 backcross of BALB/cMed and C57BL/6J mice. A major modifier was localized within a 10 cM interval on chromosome 7. The effect of the locus on DNA damage responses was examined in the parental strains and mice that are congenic for C57BL/6J alleles on the BALB/cMed background (SM1- Trp53 +/− ). The mammary epithelium of C57BL/6J- Trp53 +/− females exhibited little radiation-induced apoptosis compared to BALB/cMed- Trp53 +/− and SM1- Trp53 +/− females indicating that the Suprmam1 B6/B6 alleles could not rescue repair of radiation-induced DNA double-strand breaks mostly relying on non-homologous end joining. In contrast, the Suprmam1 B6/B6 alleles in SM1- Trp53 +/− mice were sufficient to confer the C57BL/6J- Trp53 +/− phenotypes in homology-directed repair and replication fork progression. The Suprmam1 B6/B6 alleles in SM1- Trp53 +/− mice appear to act in trans to regulate a panel of DNA repair and replication genes which lie outside the locus. Significance: Genetic variation in replication-associated DNA repair can modify consequences of heterozygous mutations in Trp53 and contribute to susceptibility to mammary tumors in mouse models of Li-Fraumeni syndrome.

Impact of Simulated Rotating Shift Work on Mammary Tumor Development in the p53R270H©/+WAPCre Mouse Model for Breast Cancer

“…It is important to note that the strain of mice can influence tumor type in p53-deficient mice. For example, BALB/c mice tend to show a different tumor spectrum (Chan et al, 2021; Majhi et al, 2021), with a relatively high percentage of adenosarcomas compared with several other genetic backgrounds (such as A/J mice).…”

The levels of p53 govern the hierarchy of DNA damage tolerance pathway usage

“…In the light of the relevance that the context such as differentiation status, species or strain may have for the POLι-p53 DDT pathway choice ( 38 , 45 ) and because of p53′s remarkable capability to adapt to cellular insults through rapid changes in its level ( 1 ), we sought to explore the impact that changes in p53 levels may have on the DDT pathway choices during unperturbed growth, i.e. without exogenous DNA damage treatment.…”

SEOM clinical guideline on heritable TP53-related cancer syndrome (2022)

“…In contrast, debate continues regarding phenotype-genotype correlation associated with loss of function and non-dominant negative variants [ 1 , 11 , 12 ]. Also, the different penetrance among carriers from the same family suggests the coexistence of genetic and environmental modifiers [ 13 , 14 ].…”