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Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer
J Jonkers1, R Meuwissen, H van der Gulden
1Division of Molecular Genetics and Centre of Biomedical Genetics, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Abstract:
Inheritance of one defective BRCA2 allele predisposes humans to breast cancer. To establish a mouse model for BRCA2-associated breast cancer, we generated mouse conditional mutants with BRCA2 and/or p53 inactivated in various epithelial tissues, including mammary-gland epithelium. Although no tumors arose in mice carrying conditional Brca2 alleles, mammary and skin tumors developed frequently in females carrying conditional Brca2 and Trp53 alleles. The presence of one wildtype Brca2 allele resulted in a markedly delayed tumor formation; loss of the wildtype Brca2 allele occurred in a subset of these tumors. Our results show that inactivation of BRCA2 and of p53 combine to mediate mammary tumorigenesis, and indicate that disruption of the p53 pathway is pivotal in BRCA2-associated breast cancer.
Insights
Mice with inactivated BRCA2 and p53 genes developed frequent mammary and skin tumors. Loss of the wild-type BRCA2 allele was observed in some tumors, highlighting the critical role of p53 in BRCA2-associated breast cancer.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Inheriting a defective BRCA2 gene increases human breast cancer risk.
- Understanding the genetic basis of BRCA2-associated cancers is crucial for developing effective treatments.
Purpose of the Study:
- To create a mouse model for studying BRCA2-associated breast cancer.
- To investigate the combined roles of BRCA2 and p53 in mammary tumorigenesis.
Main Methods:
- Generated conditional mouse mutants with inactivated BRCA2 and/or p53 genes.
- Focused inactivation on epithelial tissues, including mammary glands.
- Observed tumor development and genetic alterations in the mouse models.
Main Results:
- Mice with conditional Brca2 alleles alone did not develop tumors.
- Mammary and skin tumors frequently developed in mice with conditional Brca2 and Trp53 alleles.
- Loss of the wild-type Brca2 allele was detected in a subset of tumors, delaying onset.
Conclusions:
- Inactivation of BRCA2 and p53 cooperate to drive mammary tumorigenesis.
- Disruption of the p53 pathway is essential for BRCA2-associated breast cancer development.
- This mouse model provides insights into the mechanisms of BRCA2-related cancers.