Abstract
Almost half of all hereditary breast cancers (BCs) are associated with germ-line mutations in homologous recombination (HR) genes. However, the tumor phenotypes associated with different HR genes vary, making it difficult to define the role of HR in BC predisposition. To distinguish between HR-dependent and -independent features of BCs, we generated a mouse model in which an essential HR gene, Rad51c, is knocked-out specifically in epidermal tissues. Rad51c is one of the key mediators of HR and a well-known BC predisposition gene. Here, we demonstrate that deletion of Rad51c invariably requires inactivation of the Trp53 tumor suppressor (TP53 in humans) to produce mammary carcinomas in 63% of female mice. Nonetheless, loss of Rad51c shortens the latency of Trp53-deficient mouse tumors from 11 to 6 months. Remarkably, the histopathological features of Rad51c-deficient mammary carcinomas, such as expression of hormone receptors and luminal epithelial markers, faithfully recapitulate the histopathology of human RAD51C-mutated BCs. Similar to other BC models, Rad51c/p53 double-mutant mouse mammary tumors also reveal a propensity for genomic instability, but lack the focal amplification of the Met locus or distinct mutational signatures reported for other HR genes. Using the human mammary epithelial cell line MCF10A, we show that deletion of TP53 can rescue RAD51C-deficient cells from radiation-induced cellular senescence, whereas it exacerbates their centrosome amplification and nuclear abnormalities. Altogether, our data indicate that a trend for genomic instability and inactivation of Trp53 are common features of HR-mediated BCs, whereas histopathology and somatic mutation patterns are specific for different HR genes.
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Acknowledgements
We thank Pekka Ellonen, Maija Lepistö, Sonja Lagström, and the rest of the FIMM sequencing unit for advice and sequencing of tumor samples, the pathology unit of the Haartman Institute for histology services, Sami Blom and Dr Johan Lundin for scanning histological slides. We are grateful to Dr Shyam Sharan and Dr Madalena Tarsounas for providing critical comments on the manuscript. Financial support for the project was provided to SGK by the Academy of Finland, Finnish Medical Foundation, Sigrid Juselius Foundation, Cancer Society of Finland, and Biocenter Finland. MT was supported by a fellowship from the Helsinki Doctoral Program in Biomedicine (DPBM), and the Academy of Finland.
Author contributions
MT designed and performed all experiments, analyzed the data, and wrote the manuscript. PMM and AH assisted with animal handling and histology. HE performed CNV analysis. SE analyzed tumor somatic mutations. SGK designed and supervised the project, and wrote the manuscript. All authors reviewed the manuscript.
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Tumiati, M., Munne, P., Edgren, H. et al. Rad51c- and Trp53-double-mutant mouse model reveals common features of homologous recombination-deficient breast cancers. Oncogene 35, 4601–4610 (2016). https://doi.org/10.1038/onc.2015.528
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DOI: https://doi.org/10.1038/onc.2015.528