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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| Published in: | Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 29; p. 12111 |
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| Main Authors: | , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
17.07.2007
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| Subjects: | |
| ISSN: | 0027-8424 |
| Online Access: | Get more information |
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| 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. |
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| AbstractList | 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. 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.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. |
| Author | Wessels, Lodewyk F A Liu, Xiaoling van der Gulden, Hanneke Berns, Anton Treur-Mulder, Marcelle Peterse, Johannes L Velds, Arno Jonkers, Jos Holstege, Henne Zevenhoven, John van Vliet, Martin H Kerkhoven, Ron M |
| Author_xml | – sequence: 1 givenname: Xiaoling surname: Liu fullname: Liu, Xiaoling organization: Division of Molecular Biology Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands – sequence: 2 givenname: Henne surname: Holstege fullname: Holstege, Henne – sequence: 3 givenname: Hanneke surname: van der Gulden fullname: van der Gulden, Hanneke – sequence: 4 givenname: Marcelle surname: Treur-Mulder fullname: Treur-Mulder, Marcelle – sequence: 5 givenname: John surname: Zevenhoven fullname: Zevenhoven, John – sequence: 6 givenname: Arno surname: Velds fullname: Velds, Arno – sequence: 7 givenname: Ron M surname: Kerkhoven fullname: Kerkhoven, Ron M – sequence: 8 givenname: Martin H surname: van Vliet fullname: van Vliet, Martin H – sequence: 9 givenname: Lodewyk F A surname: Wessels fullname: Wessels, Lodewyk F A – sequence: 10 givenname: Johannes L surname: Peterse fullname: Peterse, Johannes L – sequence: 11 givenname: Anton surname: Berns fullname: Berns, Anton – sequence: 12 givenname: Jos surname: Jonkers fullname: Jonkers, Jos |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/17626182$$D View this record in MEDLINE/PubMed |
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| Snippet | Women carrying germ-line mutations in BRCA1 are strongly predisposed to developing breast cancers with characteristic features also observed in sporadic... |
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| SubjectTerms | 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 |
| Title | Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer |
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