Nature Genetics
22, 37 - 43 (1999)
doi:10.1038/8743
Conditional mutation of Brca1 in mammary epithelial cells results
in blunted ductal morphogenesis and tumour formationXiaoling Xu1, Kay-Uwe Wagner2, Denise Larson3, Zoë Weaver4, Cuiling Li1, Thomas Ried4, Lothar Hennighausen2, Anthony Wynshaw-Boris3
& Chu-Xia Deng11
Genetics of Development and Disease Branch, 10/9N105, National Institutes of Health, Bethesda, Maryland 20892, USA. 2
Laboratory of Genetics and Physiology, National nstitute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. 3
Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. 4
Genetics Department, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Correspondence should be addressed to Chu-Xia Deng chuxiad@bdg10.niddk.nih.govCre-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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