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Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation

Abstract

Cre-mediated excision of exon 11 of the breast-tumour suppressor gene Brca1 in mouse mammary epithelial cells causes increased apoptosis and abnormal ductal development. Mammary tumour formation occurs after long latency and is associated with genetic instability characterized by aneuploidy, chromosomal rearrangements or alteration of Trp53 (encoding p53) transcription. To directly test the role of p53 in Brca1-associated tumorigenesis, we introduced a Trp53-null allele into mice with mammary epithelium-specific inactivation of Brca1. The loss of p53 accelerated the formation of mammary tumours in these females. Our results demonstrate that disruption of Brca1 causes genetic instability and triggers further alterations, including the inactivation of p53, that lead to tumour formation.

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Figure 1: Introduction of loxP sites into Brca1.
Figure 2: Deletion of Brca1 exon 11 in the mammary gland by Wap-Cre -mediated recombination.
Figure 3: Abnormal mammary gland development in Brca1Ko/CoWap-Cre (a,c,e,f,g,i) and control ( b,d,h,j) mice.
Figure 4: Abnormal mammary gland development in Brca1Ko/CoMMTV-Cre mice.
Figure 5: Tissue-specific mutant of Brca1 results in mammary-gland tumour formation.
Figure 6: Genetic instability in tumours.
Figure 7: Tumorigenesis in mammary-gland-specific disruption of Brca1.

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Acknowledgements

We thank H. Gu for pMC1-Cre and L. Donehower for Trp53–/– mice; J. Gotay and L. Garrett for technical assistance; D.E. Green for assistance with morphological characterization of mammary gland tumours; and S.G. Brodie, G. Robinson, F. Scotts and H. Varmus for critically reading the manuscript. K.U.W. was supported through funding by the DFG (Wa 1119/1-1).

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Correspondence to Chu-Xia Deng.

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Xu, X., Wagner, KU., Larson, D. et al. Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation. Nat Genet 22, 37–43 (1999). https://doi.org/10.1038/8743

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