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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Drug Discovery and Molecular Pharmacology Study Section (DMP)
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Misra, Raj N
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Georgetown University
Internal Medicine/Medicine
Schools of Medicine
United States
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Nathan, Shyam; Ma, Yongxian; Tomita, York A et al. (2017) BRCA1-mimetic compound NSC35446.HCl inhibits IKKB expression by reducing estrogen receptor-? occupancy in the IKKB promoter and inhibits NF-?B activity in antiestrogen-resistant human breast cancer cells. Breast Cancer Res Treat 166:681-693
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Ma, Yongxian; Tomita, York; Preet, Anju et al. (2014) Small-molecule ""BRCA1-mimetics"" are antagonists of estrogen receptor-?. Mol Endocrinol 28:1971-86
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