Inherited mutations of the breast and ovary cancer susceptibility gene-1 (BRCA1) confer a significantly increased risk for prostate cancer in male probands; but it is not known if and how BRCA1 regulates the function of prostate cancer cells. Our preliminary studies indicate that wild-type and mutant BRCA1 transgenes differentially modulate multiple phenotypic characteristics of human prostate cancer cell line DU-145, including cell proliferation, in vivo tumor growth, susceptibility to apoptosis, DNA repair activity, and estrogen receptor activity. Some of the phenotypic alterations induced by BRCA1 may be due, in part, to alterations in the expression of key regulatory proteins, including p300, Bcl-2, BRCA2, p21WAF1/CIP1, and Mdm-2. We hypothesize that BRCA1 functions as a prostate tumor suppressor gene by inhibiting cell proliferation, enhancing cellular susceptibility to apoptosis, and reducing cell sensitivity to androgen. In this application, we propose to further investigate the mechanism(s) underlying BRCA1-induced cellular alterations in several different prostate cancer cell lines. We will identify key regions of the BRCA1 molecule involved in modulation of prostate cancer cell proliferation, DNA damage response, expression of important cellular regulatory proteins, and androgen receptor activity. The knowledge from these studies will help to: 1) elucidate mechanisms that may be common to hereditary and sporadic human prostate carcinogenesis; and 2) provide an experimental basis for targetting prostate cancers by enhancing their sensitivity to cytotoxic agents, using BRCA1 gene therapy-related approaches.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA080000-02
Application #
6173750
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
Pelroy, Richard
Project Start
1999-09-01
Project End
2003-05-31
Budget Start
2000-08-04
Budget End
2001-05-31
Support Year
2
Fiscal Year
2000
Total Cost
$196,904
Indirect Cost
Name
Long Island Jewish Medical Center
Department
Type
DUNS #
City
New Hyde Park
State
NY
Country
United States
Zip Code
11040
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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
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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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