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Multiple genetic changes are associated with mammary tumorigenesis in Brca1 conditional knockout mice
S G Brodie1, X Xu, W Qiao
1Genetics of Development and Disease Branch, 10/9N105, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Oncogene
|December 26, 2001
Summary
Somatic mutations in the BRCA1 gene rarely cause sporadic cancers. Mouse models show that Brca1 disruption leads to diverse mammary tumors with genetic alterations, suggesting multiple factors in tumorigenesis.
Area of Science:
- Oncology
- Genetics
- Cancer Biology
Background:
- Germline mutations in BRCA1 predispose women to breast cancer.
- Somatic mutations in BRCA1 are infrequent in sporadic cancers, a phenomenon not fully understood.
Purpose of the Study:
- To investigate the role of Brca1 in mammary tumorigenesis using mouse models.
- To identify genetic and molecular alterations associated with Brca1-deficient mammary tumors.
Main Methods:
- Conditional disruption of Brca1 in mouse mammary epithelium on p53 wild type and heterozygous backgrounds.
- Analysis of tumor histopathology, chromosome abnormalities, and molecular alterations (gene expression, translocations).
- Generation and characterization of cell lines from Brca1-associated mammary tumors.
Main Results:
- Brca1 disruption in mice led to mammary tumors with diverse histopathology and severe chromosome abnormalities.
- Tumors exhibited overexpression of ErbB2, c-Myc, p27, and Cyclin D1, with loss of ERalpha and p16.
- Translocations involving p53 were observed, leading to abnormal RNA and protein products.
- Cultured tumor cells retained genetic changes and showed resistance to Tamoxifen but sensitivity to Doxorubicin or gamma-irradiation.
Conclusions:
- Multiple factors beyond p53 mutations likely contribute to Brca1-related mammary tumorigenesis.
- Identified genetic alterations may play key roles in the development of Brca1-associated tumors.
- Doxorubicin or gamma-irradiation show potential as effective treatments for Brca1-deficient mammary tumors.