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

Oncogene volume 40, pages 5026–5037 (2021)Cite this article

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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 Suprmam1B6/B6 alleles could not rescue repair of radiation-induced DNA double-strand breaks mostly relying on non-homologous end joining. In contrast, the Suprmam1B6/B6 alleles in SM1-Trp53+/− mice were sufficient to confer the C57BL/6J-Trp53+/− phenotypes in homology-directed repair and replication fork progression. The Suprmam1B6/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.

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Fig. 1: Linkage analysis of mammary tumor incidence in BALB/cMed mice.
Fig. 2: Haplotype blocks differing between BALB/cMed and strains that do not develop mammary tumors.
Fig. 3: Generation and validation of BALB/cMed.B6-Suprmam1(N10)-Trp53tm1Tyj/+ (SM1-Trp53+/−) strain.
Fig. 4: Variation to radiation sensitivity between strains.
Fig. 5: Single-strand annealing and gene expression differences between C57BL/6-Trp53+/−, SM1-Trp53+/−, and BALB/c-Trp53+/− MEFs.
Fig. 6: Difference in replication fork processivity between C57BL/6-Trp53+/−, SM1-Trp53+/−, and BALB/c-Trp53+/− MEFs.

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Acknowledgements

Research reported in this publication was supported, in part, by the National Institute of Environmental Health Sciences of the National Institutes of Health under award number R01CA105452 (DJJ), U01ES026140 (DJJ, SSS), the Department of Defense under contract #W81XWH-15-1-0217 (DJJ) and the Rays of Hope Center for Breast Cancer Research (DJJ), University Grants Commission (India) for Raman Fellowship for post-doctoral research (PDM) as well as by the German Research Foundation (DFG, Research Training Group 2554 to LW) and by the DFG-funded Graduate School of Molecular Medicine, Ulm University (PhD fellowship to KJM).

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Authors and Affiliations

  1. Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, Amherst, MA, USA

    Prabin Dhangada Majhi, Nicholas B. Griner, Shannon Compton, Trevor A. Baptiste, Karen A. Dunphy, Amy L. Roberts & D. Joseph Jerry

  2. Department of Botany, Ravenshaw University, Cuttack, Odisha, India

    Prabin Dhangada Majhi

  3. Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, MA, USA

    Jacob A. Mayfield

  4. Department of Microbiology, University of Massachusetts Amherst, Amherst, MA, USA

    Jeffrey J. Kane

  5. Department of Surgery, University of Massachusetts Medical School-Baystate, Springfield, MA, USA

    Sallie S. Schneider

  6. Pioneer Valley Life Sciences Institute, Springfield, MA, USA

    Sallie S. Schneider & D. Joseph Jerry

  7. Genome Explorations, Memphis, TN, USA

    Evan M. Savage & Divyen Patel

  8. John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia

    Anneke C. Blackburn

  9. Department of Obstetrics and Gynecology, Ulm University, Ulm, Germany

    Kim Joana Maurus & Lisa Wiesmüller

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Majhi, P.D., Griner, N.B., Mayfield, J.A. et al. Genetic modifiers regulating DNA replication and double-strand break repair are associated with differences in mammary tumors in mouse models of Li-Fraumeni syndrome. Oncogene 40, 5026–5037 (2021). https://doi.org/10.1038/s41388-021-01892-5

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