Tumor Suppressor Mechanism in Breast Cancer: Studies in Genetically Engineered Mice
Abstract
The p53 and pRb tumor suppressor pathways are frequently altered in human breast cancer. Although animal models have begun to explore mechanisms for these proteins, the roles can be different depending on the cancer type. The mechanisms by which p53 and pRb suppress tumorigenesis in breast cancer remain unclear. Our previous studies in a mouse brain epithelial tumor model have demonstrated the importance of pRb in tumor initiation and of p53 in tumorprogression, and have also established p53-dependent apoptosis as a means of tumor suppression. In this model, brain cells are induced to proliferate aberrantly by tissue-specific expression of T121, a modified T antigen oncoprotein that inactivates pRb. This causes slow-growing, but highly apoptotic tumors. Further inactivation of p53 causes a dramatic decline in cell teath and rapid acceleration of tumor growth. Here, we propose similar studies to examine the pRb and p53 roles in breast cancer. The full T antigen oncoprotein (inactivates both pRb and p53) has been shown to induce mammary tumors in transgenic mice. Here the T121 oncoprotein will be tissue-specifically expressed in mammary epithelium by mammary-specific promoters to test the role of pRb. Further analysis using knock out strains will then address the role of p53 when both pRb and p53 are inactivated. Impacts of the pRb inactivation, and of coexisting pRb and p53 mutations on apoptosis, proliferation, morphology abnormalities, and neoplastic growth in mammary glands will be assessed. Such preclinical animal models are essential for progress in breast cancer research. The approach proposed here is novel because the role of pRb has not previously been tested and the p53 tumor suppression mechanism in breast cancer is not yet understood.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2000
- Accession Number
- ADA386867
Entities
People
- Terry V. Dyke
Organizations
- University of North Carolina at Chapel Hill