Project Abstract: Targeted therapies to correct genomic instability in BRCA1-deficient cells. Individuals with mutations in either the BRCA1 or BRCA2 gene account for approximately 5- 10% of all breast cancers in the developed world. For women carrying a mutant BRCA1 gene, there is a nearly 80% lifetime chance of developing breast cancer and a nearly 40% chance of developing ovarian cancer. At present, there are no effective or targeted molecular therapies that modify this susceptibility. In the absence of BRCA1 activity, cells are incapable of repairing DNA breaks through the homologous recombination pathway (HR). HR provides an error free mechanism to repair DNA damage, but in the absence of efficient HR, cells can repair DNA damage though other error-prone pathways. The use of these pathways can lead to the formation of abnormal and potentially harmful chromosomal structures that promote tumorigenesis. Indeed, it is generally believed that the inability of BRCA1 deficient cells to perform HR is central to its role in tumor formation. Recent reports have demonstrated that it is possible to restore HR activity in BRCA1 deficient cells by deletion of the gene for the DNA damage response factor, 53BP1. These results suggest that in BRCA1-deficient cells, 53BP1 may act as a molecular inhibitor of HR. Furthermore, inhibiting 53BP1 activity may reduce the incidence of BRCA1-mediated breast cancer. The proposed research will explore the novel notion that it may be possible to restore near normal HR activity in BRCA1 cells and tissues. The interplay between 53BP1 and BRCA1 will be further characterized to refine our understanding of the underlying mechanism, as well as an attempt to develop lead compounds that inhibit 53BP1 function. A fuller understanding of this phenomenon will lead to targeted therapies to reduce the lifetime risk of tumor formation in BRCA1 and potentially BRCA2 carriers.
|Effective start/end date||9/20/12 → 8/31/15|
- National Institutes of Health: $241,530.00
- National Institutes of Health: $232,652.00
- National Institutes of Health: $249,000.00