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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA080000-08
Application #
7278164
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Okano, Paul
Project Start
1999-09-01
Project End
2009-06-30
Budget Start
2007-08-22
Budget End
2008-06-30
Support Year
8
Fiscal Year
2007
Total Cost
$250,168
Indirect Cost
Name
Georgetown University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Karve, Tejaswita M; Rosen, Eliot M (2012) B-cell translocation gene 2 (BTG2) stimulates cellular antioxidant defenses through the antioxidant transcription factor NFE2L2 in human mammary epithelial cells. J Biol Chem 287:31503-14
Ma, Yongxian; Fan, Saijun; Hu, Changyan et al. (2010) BRCA1 regulates acetylation and ubiquitination of estrogen receptor-alpha. Mol Endocrinol 24:76-90
Saha, Tapas; Rih, Jeong Keun; Roy, Rabindra et al. (2010) Transcriptional regulation of the base excision repair pathway by BRCA1. J Biol Chem 285:19092-105
Katiyar, Pragati; Ma, Yongxian; Riegel, Anna et al. (2009) Mechanism of BRCA1-mediated inhibition of progesterone receptor transcriptional activity. Mol Endocrinol 23:1135-46
Fan, Saijun; Meng, Qinghui; Saha, Tapas et al. (2009) Low concentrations of diindolylmethane, a metabolite of indole-3-carbinol, protect against oxidative stress in a BRCA1-dependent manner. Cancer Res 69:6083-91
Ballal, Rahul D; Saha, Tapas; Fan, Saijun et al. (2009) BRCA1 localization to the telomere and its loss from the telomere in response to DNA damage. J Biol Chem 284:36083-98
Ballal, Rahul; Cheema, Amrita; Ahmad, Waaqar et al. (2009) Fluorescent oligonucleotides can serve as suitable alternatives to radiolabeled oligonucleotides. J Biomol Tech 20:190-4
Saha, Tapas; Rih, Jeong Keun; Rosen, Eliot M (2009) BRCA1 down-regulates cellular levels of reactive oxygen species. FEBS Lett 583:1535-43
Ma, Yongxian; Katiyar, Pragati; Jones, Laundette P et al. (2006) The breast cancer susceptibility gene BRCA1 regulates progesterone receptor signaling in mammary epithelial cells. Mol Endocrinol 20:14-34
Fan, S; Meng, Q; Auborn, K et al. (2006) BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells. Br J Cancer 94:407-26

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