Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer

Women carrying germ-line mutations in BRCA1 are strongly predisposed to developing breast cancers with characteristic features also observed in sporadic basal-like breast cancers. They appear as high-grade tumors with high proliferation rates and pushing borders. On the molecular level, they are neg...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 29; p. 12111
Main Authors: Liu, Xiaoling, Holstege, Henne, van der Gulden, Hanneke, Treur-Mulder, Marcelle, Zevenhoven, John, Velds, Arno, Kerkhoven, Ron M, van Vliet, Martin H, Wessels, Lodewyk F A, Peterse, Johannes L, Berns, Anton, Jonkers, Jos
Format: Journal Article
Language:English
Published: United States 17.07.2007
Subjects:
Alleles
Animals
Biomarkers, Tumor - metabolism
BRCA1 Protein - deficiency
Breast Neoplasms - pathology
Cluster Analysis
Epithelial Cells - pathology
Female
Genomic Instability - genetics
Humans
Loss of Heterozygosity
Mammary Neoplasms, Animal - classification
Mammary Neoplasms, Animal - pathology
Mice
Mutation - genetics
Species Specificity
Tumor Suppressor Protein p53 - deficiency
ISSN:0027-8424
Online Access:Get more information
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Summary:Women carrying germ-line mutations in BRCA1 are strongly predisposed to developing breast cancers with characteristic features also observed in sporadic basal-like breast cancers. They appear as high-grade tumors with high proliferation rates and pushing borders. On the molecular level, they are negative for hormone receptors and ERBB2, display frequent TP53 mutations, and express basal epithelial markers. To study the role of BRCA1 and P53 loss of function in breast cancer development, we generated conditional mouse models with tissue-specific mutation of Brca1 and/or p53 in basal epithelial cells. Somatic loss of both BRCA1 and p53 resulted in the rapid and efficient formation of highly proliferative, poorly differentiated, estrogen receptor-negative mammary carcinomas with pushing borders and increased expression of basal epithelial markers, reminiscent of human basal-like breast cancer. BRCA1- and p53-deficient mouse mammary tumors exhibit dramatic genomic instability, and their molecular signatures resemble those of human BRCA1-mutated breast cancers. Thus, these tumors display important hallmarks of hereditary breast cancers in BRCA1-mutation carriers.
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ISSN:0027-8424
DOI:10.1073/pnas.0702969104