Background: Inherited mutations of the breast cancer susceptibility gene-1 (BRCA1) confer a high risk for breast cancer, ovarian cancer, and other tumor types. Accumulating evidence suggests that down-regulation or functional inactivation of BRCA1 plays a role in the development of sporadic (non-hereditary) cancers. BRCA1 plays roles in the regulation of cell cycle progression and DNA repair. However, the molecular bases for these roles are unclear, nor is it known if BRCA1 exerts other functions in cancer suppression. Preliminary Studies: During the initial grant period, we made great progress in understanding the molecular actions of BRCA1. We identified roles for BRCA1 in regulating the telomerase enzyme and telomere length and stability. We also demonstrated a role for BRCA1 in regulating the heat shock response and expression of a small heat shock protein, HSP27. We developed small interfering RNAs to non-toxically deplete BRCA1, allowing us to study the biological functions of endogenous BRCA1. We used DNA microarray analyses to identify novel BRCA1-regulated genes, including genes implicated in the antioxidant response; and we documented functional roles for BRCA1 in protecting cells against oxidative stress. Hypothesis: BRCA1 functions to preserve genomic and proteomic integrity via several distinct mechanisms that converge at common points: 1) stabilization of telomeres; and 2) stimulating antioxidant defenses. Conversely, loss of these functions promotes genomic/proteomic instability, leading to tumorigenesis.
Research Aims : The major goals of this project are: SA1. To delineate the roles of BRCA1 in TERT regulation and telomere maintenance; SA2. To assess the mechanism(s) by which BRCA1 protects cells against oxidative stress in cultured cells; and SA3. To perform physiologic confirmatory studies on the role of BRCA1 in the antioxidant response in vivo in an experimental animal model. Significance: The focus of this competing continuation is to further elucidate the molecular function of BRCA1, particularly in mammary epithelial cell types. Using insights gained during the initial period, we will extend our knowledge of the molecular basis of the tumor suppressor activity of BRCA1. The roles of BRCA1 in telomere regulation and the antioxidant response also have implications for aging research. It is hoped that knowledge gained from these studies will lead to new approaches to cancer control and treatment.
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