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.

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Targeted therapies to correct genomic instability in BRCA1-deficient cells. The subject of this study is BRCA1-deficient breast cancer. Depending on ethnicity, between 0.5% and 8.3% of breast cancer cases are associated with mutation in the Breast Cancer Associated 1 (BRCA1) gene. Women who carry mutations in BRCA1 have a particularly high risk of developing breast (estimated 57% lifetime risk) or ovarian (40% lifetime risk) cancers. Although BRCA1 mutation is not a feature of the majority of breast cancer cases, patients with BRCA1 mutations have earlier onset of disease and a high incidence of the 'triple negative'phenotype which carries a poor prognosis. There is presently no targeted therapy that significantly impacts the rate of tumor development for individuals carrying an inherited susceptibility for breast cancer. The recent development of PARP inhibitors that exploit the absence of homologous recombination (HR) activity in BRCA1 and BRCA2 -mutant cells represents an enormous step forward in targeted therapy, however, an even more effective strategy would be to prevent or delay the development of tumors in the first place. Somatic cells that have no functioning BRCA1 allele are defective for HR, leading to a failure to properly repair DNA damage and a propensity for further genomic instability that promotes tumorigenesis. The restoration of HR activity in BRCA1 deficient cells and tissues has generally been viewed as clearly advantageous, as it would prevent genomic instability in cells lacking BRCA1 function. However, restoring HR has also been assumed to be impossible, based on the known requirement of BRCA1 for HR. Recent data challenge this long held assumption by demonstrating a near total recovery of HR activity in BRCA1 deficient cells that contain the simultaneous deletion of 53BP1. Furthermore, in vivo mouse data show that this restoration of HR activity in BRCA1 deficient tissues significantly reduces the incidence of breast cancer. The goal of this proposal is to exploit these paradigm-shifting observations. Using mouse genetics to find DNA damage response factors that influence the use of the error-free HR pathway, new targets for clinical intervention in cancer will be found. The proposed research will also aim to identify small molecule inhibitors that prevent 53BP1 binding to chromatin, thereby restoring HR function in BRCA1-deficient cells and reducing the risk of tumorigensis. These agents will be lead compounds for an entirely novel approach to treating BRCA1 deficiency, based on preventing tumorigenesis by restoring HR function in BRCA1 deficient cells.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Pelroy, Richard
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Rutgers University
Schools of Arts and Sciences
New Brunswick
United States
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