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Loss of Heterozygosity Occurs via Mitotic Recombination in Trp53^+/– Mice and Associates with Mammary Tumor Susceptibility of the BALB/c Strain

¹ Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, Massachusetts; Departments of ² Cytogenetics and ³ Pathology, Baystate Medical Center, Springfield, Massachusetts; ⁴ Department of Molecular and Human Genetics and ⁵ Division of Molecular Virology, Baylor College of Medicine, Houston, Texas; ⁶ Spectral Genomics, Houston, Texas; and ⁷ Department of Obstetrics and Gynecology, Louisiana State University Health Sciences Center, Shreveport, Louisiana

Loss of heterozygosity (LOH) occurs commonly in cancers causing disruption of tumor suppressor genes and promoting tumor progression. BALB/c-Trp53^+/– mice are a model of Li-Fraumeni syndrome, exhibiting a high frequency of mammary tumors and other tumor types seen in patients. However, the frequency of mammary tumors and LOH differs among strains of Trp53^+/– mice, with mammary tumors occurring only on a BALB/c genetic background and showing a high frequency of LOH, whereas Trp53^+/– mice on a 129/Sv or (C57BL/6 x 129/Sv) mixed background have a very low frequency of mammary tumors and show LOH for Trp53 in only 50% of tumors. We have performed studies on tumors from Trp53^+/– mice of several genetic backgrounds to examine the mechanism of LOH in BALB/c-Trp53^+/– mammary tumors. By Southern blotting, 96% (24 of 25) of BALB/c-Trp53^+/– mammary tumors displayed LOH for Trp53. Karyotype analysis indicated that cells lacking one copy of chromosome 11 were present in all five mammary tumors analyzed but were not always the dominant population. Comparative genomic hybridization analysis of these five tumors indicated either loss or retention of the entire chromosome 11. Thus chromosome loss or deletions within chromosome 11 do not account for the LOH observed by Southern blotting. Simple sequence length polymorphism analysis of (C57BL/6 x BALB/c) F1-Trp53^+/– mammary tumors showed that LOH occurred over multiple loci and that a combination of maternal and paternal alleles were retained, indicating that mitotic recombination is the most likely mechanism of LOH. Nonmammary tumors of BALB/c mice also showed a high frequency of LOH (22 of 26, 85%) indicating it was not a mammary tumor specific phenomenon but rather a feature of the BALB/c strain. In (C57BL/6 x BALB/c) F1-Trp53^+/– mice LOH was observed in 93% (13 of 14) of tumors, indicating that the high frequency of LOH was a dominant genetic trait. Thus the high frequency of LOH for Trp53 in BALB/c-Trp53^+/– mammary tumors occurs via mitotic recombination and is a dominant genetic trait that associates with the occurrence of mammary tumors in (C57BL/6 x BALB/c) F1-Trp53^+/– mice. These results further implicate double-strand DNA break repair machinery as important contributors to mammary tumorigenesis.

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