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PMID: 17626182 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 104 ·No. 29 ·2007-07-17 ·Pages 12111-6

Liu X, Holstege H, van der Gulden H, Treur-Mulder M, Zevenhoven J, Velds A, Kerkhoven RM, van Vliet MH, Wessels LF, Peterse JL, Berns A, Jonkers J

Abstract

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.

MeSH Terms
Alleles Animals BRCA1 Protein/deficiency Biomarkers, Tumor/metabolism Breast Neoplasms/pathology Cluster Analysis Epithelial Cells/pathology Female Genomic Instability/genetics Humans Loss of Heterozygosity Mammary Neoplasms, Animal/classification,pathology Mice Mutation/genetics Species Specificity Tumor Suppressor Protein p53/deficiency
Chemicals
BRCA1 Protein Biomarkers, Tumor Tumor Suppressor Protein p53
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Liu Xiaoling
Division of Molecular Biology Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
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
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0702969104
Published
2007-07-17
Epub
2007-00-11
Pages
12111-6
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1924557
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.0702969104 PMC Full Text View journal details
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