A mouse model featuring tissue-specific deletion of p53 and Brca1 gives rise to mammary tumors with genomic and transcriptomic similarities to human basal-like breast cancer.
Breast Cancer Res Treat
; 174(1): 143-155, 2019 Feb.
Article
em En
| MEDLINE
| ID: mdl-30484104
ABSTRACT
PURPOSE AND METHODS:
In human basal-like breast cancer, mutations and deletions in TP53 and BRCA1 are frequent oncogenic events. Thus, we interbred mice expressing the CRE-recombinase with mice harboring loxP sites at TP53 and BRCA1 (K14-Cre; p53f/f Brca1f/f) to test the hypothesis that tissue-specific deletion of TP53 and BRCA1 would give rise to tumors reflective of human basal-like breast cancer.RESULTS:
In support of our hypothesis, these transgenic mice developed tumors that express basal-like cytokeratins and demonstrated intrinsic gene expression features similar to human basal-like tumors. Array comparative genomic hybridization revealed a striking conservation of copy number alterations between the K14-Cre; p53f/f Brca1f/f mouse model and human basal-like breast cancer. Conserved events included MYC amplification, KRAS amplification, and RB1 loss. Microarray analysis demonstrated that these DNA copy number events also led to corresponding changes in signatures of pathway activation including high proliferation due to RB1 loss. K14-Cre; p53f/f Brca1f/f also matched human basal-like breast cancer for a propensity to have immune cell infiltrates. Given the long latency of K14-Cre; p53f/f Brca1f/f tumors (~ 250 days), we created tumor syngeneic transplant lines, as well as in vitro cell lines, which were tested for sensitivity to carboplatin and paclitaxel. These therapies invoked acute regression, extended overall survival, and resulted in gene expression signatures of an anti-tumor immune response.CONCLUSION:
These findings demonstrate that this model is a valuable preclinical resource for the study of human basal-like breast cancer.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteína Supressora de Tumor p53
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Proteínas Supressoras de Tumor
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Modelos Animais de Doenças
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Neoplasias Mamárias Experimentais
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Breast Cancer Res Treat
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos