Background. Inherited mutations of the breast cancer susceptibility gene-1 (BRCA1) confer a high risk for specific tumor types, including breast and ovarian cancers. BRCA1 plays roles in the regulation of DNA repair, cell cycle progression, apoptosis, and gene transcription. But these generic actions do not explain why BRCA1 mutations lead to specific tumor types, such as breast cancer. We have been studying a mammary tissue-specific action of BRCA1 [ie., its ability to repress estrogen receptor (ER-alpha signaling) that may, in part, explain why BRCA1 mutations are associated with estrogen (E2)-dependent tumor types (eg., breast, endometrial, and cervical cancers). Preliminary Studies. During the initial funding period, we have completed and gone beyond the original proposed objectives in understanding the mechanisms by which the BRCA1 regulates estrogen action. In new preliminary studies, we mapped the interacting sites between the BRCA1 and ER-alpha proteins at a high resolution. And we adduced evidence for two distinct mechanisms by which the ER-alpha regulatory function of BRCA1 can be inactivated: 1) through oncogenic signaling pathways (eg., over-expression of cyclin D1, c-Myc, and the c-Akt kinase); and 2) via a tumor-associated mutation of an acetylation site within the hinge region of ER-alpha. Finally, we generated preliminary evidence that exogenous E2 induces mammary hyperplasia and preneoplasia in Brca1-deficient mice. Hypothesis. BRCA1 prevents breast cancer, in part, by inhibition of ER-alpha activity and, in part, by estrogen (E2)-independent actions (ie., by its function as a """"""""caretaker"""""""" gene, to prevent genomic instability). The E2-dependent and E2-independent functions of BRCA1 are distinct and can be structurally dissociated. Finally, the ability of BRCA1 to repress ER-alpha can be functionally inactivated by oncoproteins and growth factor signaling pathways.
Research Aims. The major goals of this project are: SA1. To precisely identify the molecular determinants of the BRCA1:ER-alpha interaction; SA2. To determine the mechanisms by which oncogene signaling rescues BRCA1 inhibition of ER-alpha. SA3. To determine the role of acetylation in regulating ER-alpha resistance to inhibition by BRCA1; and SA4. To examine the interaction between estrogen and Brca1 in mammary tumorigenesis in vivo. Significance. These studies address a major mechanism by which BRCA1 inactivation leads to breast cancer: namely, deregulation of ER-alpha signaling. They are relevant to the pathogenesis of both hereditary and sporadic breast cancers. Thus, sporadic breast cancers frequently exhibit absent or reduced expression of BRCA1; and we found that knockdown of endogenous BRCA1 by RNA interference causes ligand-independent activation of ER-alpha. In addition to their implications for breast cancer pathogenesis, these studies are of practical importance, since they may suggest novel approaches for breast cancer prevention and treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA082599-08
Application #
7148082
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Woodhouse, Elizabeth
Project Start
1999-07-01
Project End
2009-11-30
Budget Start
2006-12-28
Budget End
2007-11-30
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
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
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; Hu, Changyan; Riegel, Anna T et al. (2007) Growth factor signaling pathways modulate BRCA1 repression of estrogen receptor-alpha activity. Mol Endocrinol 21:1905-23
Xu, J; Gao, M; Fan, S et al. (2007) Effect of Akt inhibition on scatter factor-regulated gene expression in DU-145 human prostate cancer cells. Oncogene 26:2925-38
Rosen, Eliot M; Fan, Saijun; Ma, Yongxian (2006) BRCA1 regulation of transcription. Cancer Lett 236:175-85
Ma, Yongxian; Yuan, Ren-qi; Fan, Saijun et al. (2006) Identification of genes that modulate sensitivity of U373MG glioblastoma cells to cis-platinum. Anticancer Drugs 17:733-51

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