We have studied the functional interaction of the breast cancer susceptibility gene-1 (BRCA1) and the estrogen receptor (ER-1) for the past 10 years. During these studies, we observed that BRCA1 strongly inhibits ER-1 activity in breast cancer cells and blocks estrogen (E2)-stimulated gene expression and cell proliferation. The BRCA1 repression of ER-1 activity is due to a physical interaction of the BRCA1 and ER- 1 proteins, which we mapped at high resolution. From these studies, we generated a 3D model of the BRCA1: ER-1 complex and performed virtual screening of a small molecule library to identify compounds that might act as "BRCA1-mimetics" to insert deeply into ER-1 at key contact points. Of 40 such compounds that we tested, 6 strongly inhibited ER-1 activity, including several that yielded 50% inhibition at concentrations of only 3-4

Public Health Relevance

BRCA1 (breast cancer 1, early onset) is a human gene that belongs to a class of genes known as tumor suppressors, which maintain genomic integrity to prevent uncontrolled proliferation. Inherited variations (mutations) in the BRCA1 gene have been implicated in several hereditary cancer types, including breast and ovarian cancers. The goal of this research is to develop small molecule drug-like compounds that mimic the ability of the BRCA1 protein to insert into the estrogen receptor protein and inhibit estrogen action. These "BRCA1-mimetic" compounds may be useful in the prevention and/or treatment of breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA150646-03
Application #
8207275
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Misra, Raj N
Project Start
2010-02-09
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
3
Fiscal Year
2012
Total Cost
$573,566
Indirect Cost
$199,908
Name
Georgetown University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Rosen, Eliot M; Pishvaian, Michael J (2014) Targeting the BRCA1/2 tumor suppressors. Curr Drug Targets 15:17-31
Fan, Saijun; Meng, Qinghui; Xu, Jiaying et al. (2013) DIM (3,3'-diindolylmethane) confers protection against ionizing radiation by a unique mechanism. Proc Natl Acad Sci U S A 110:18650-5