Genetic modifiers regulating DNA replication and double-strand break repair are associated with differences in mammary tumors in mouse models of Li-Fraumeni syndrome
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-Frau...
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Published in | Oncogene Vol. 40; no. 31; pp. 5026 - 5037 |
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Main Authors | , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
Nature Publishing Group
05.08.2021
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Subjects | |
Online Access | Get full text |
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Summary: | 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
alleles could not rescue repair of radiation-induced DNA double-strand breaks mostly relying on non-homologous end joining. In contrast, the Suprmam1
alleles in SM1-Trp53
mice were sufficient to confer the C57BL/6J-Trp53
phenotypes in homology-directed repair and replication fork progression. The Suprmam1
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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0950-9232 1476-5594 |
DOI: | 10.1038/s41388-021-01892-5 |