Abstract
Breast cancer is a chief cause of cancer-related mortality that affects women worldwide. About 8% of cases are hereditary, and approximately half of these are associated with germline mutations of the breast tumor suppressor gene BRCA1 (refs. 1,2). We have previously reported a mouse model in which Brca1 exon 11 is eliminated in mammary epithelial cells through Cre-mediated excision3. This mutation is often accompanied by alterations in transformation-related protein 53 (Trp53, encoding p53), which substantially accelerates mammary tumor formation. Here, we sought to elucidate the underlying mechanism(s) using mice deficient in the Brca1 exon 11 isoform (Brca1Δ11/Δ11). Brca1Δ11/Δ11 embryos died late in gestation because of widespread apoptosis. Unexpectedly, elimination of one Trp53 allele completely rescues this embryonic lethality and restores normal mammary gland development. However, most female Brca1Δ11/Δ11 Trp53+/− mice develop mammary tumors with loss of the remaining Trp53 allele within 6–12 months. Lymphoma and ovarian tumors also occurr at lower frequencies. Heterozygous mutation of Trp53 decreases p53 and results in attenuated apoptosis and G1–S checkpoint control, allowing Brca1Δ11/Δ11 cells to proliferate. The p53 protein regulates Brca1 transcription both in vitro and in vivo, and Brca1 participates in p53 accumulation after γ-irradiation through regulation of its phosphorylation and Mdm2 expression. These findings provide a mechanism for BRCA1-associated breast carcinogenesis.
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Acknowledgements
We thank S.J. Korsmeyer for Bax−/− mice, L. Donehower for Trp53−/− mice, H. Westphal for EIIa-Cre transgenic mice and G. Lozano for antibody against Mdm2. We thank C. Li and B. Jeffries for technical assistance, and members of the Deng laboratory for discussions.
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Xu, X., Qiao, W., Linke, S. et al. Genetic interactions between tumor suppressors Brca1 and p53 in apoptosis, cell cycle and tumorigenesis. Nat Genet 28, 266–271 (2001). https://doi.org/10.1038/90108
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DOI: https://doi.org/10.1038/90108
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