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Article
Nature Medicine  10, 40 - 47 (2004)
Published online: 14 December 2003; | doi:10.1038/nm969

Suppression of breast cancer by chemical modulation of vulnerable zinc fingers in estrogen receptor

Li Hua Wang1, 2, 7, Xiao Yi Yang1, 7, Xiaohu Zhang1, Kelly Mihalic1, Ying-Xin Fan3, Weihua Xiao1, O M Zack Howard4, Ettore Appella5, Andrew T Maynard1, 6 & William L Farrar2

1  Basic Research Program, SAIC-Frederick, National Cancer Institute-Frederick, National Institutes of Health, PO Box B, Frederick, Maryland 21702, USA.

2  Cytokine Molecular Mechanisms Section, National Cancer Institute-Frederick, National Institutes of Health, PO Box B, Frederick, Maryland 21702, USA.

3  Division of Therapeutic Protein, Center for Biological Evaluation and Research, Food and Drug Administration, 40 Convent Drive, Bethesda, Maryland 20892, USA.

4  Laboratory of Molecular Immunoregulation, National Cancer Institute-Frederick, National Institutes of Health, PO Box B, Frederick, Maryland 21702, USA.

5  Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, 40 Convent Drive, Bethesda, Maryland 20892, USA.

6  Present address: AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, Delaware 19150, USA.

7  These authors contributed equally to this work.

Correspondence should be addressed to Li Hua Wang lhwang@ncifcrf.gov or William L Farrar farrar@ncifcrf.gov
Current antiestrogen therapy for breast cancer is limited by the mixed estrogenic and antiestrogenic activity of selective estrogen receptor modulators. Here we show that the function of zinc fingers in the estrogen receptor DNA-binding domain (DBD) is susceptible to chemical inhibition by electrophilic disulfide benzamide and benzisothiazolone derivatives, which selectively block binding of the estrogen receptor to its responsive element and subsequent transcription. These compounds also significantly inhibit estrogen-stimulated cell proliferation, markedly reduce tumor mass in nude mice bearing human MCF-7 breast cancer xenografts, and interfere with cell-cycle and apoptosis regulatory gene expression. Functional assays and computational analysis support a molecular mechanism whereby electrophilic agents preferentially disrupt the vulnerable C-terminal zinc finger, thus suppressing estrogen receptor−mediated breast carcinoma progression. Our results provide the proof of principle for a new strategy to inhibit breast cancer at the level of DNA binding, rather than the classical antagonism of estrogen binding.

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Nature Medicine
ISSN: 1078-8956
EISSN: 1546-170X
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