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

Abstract

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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Figure 1: Inhibition of estrogen-mediated breast cancer cell proliferation by DIBA and BITA.
Figure 2: In vivo efficacy and specificity of DIBA in breast cancer growth and gene expression.
Figure 3: Interaction of electrophilic agents with estrogen receptor zinc fingers.
Figure 4: Electrophilic agents inhibit ERE DNA binding and transactivation.
Figure 5: Diverse effects of electrophilic agents on nuclear receptors.
Figure 6: Specificity of estrogen receptor zinc finger inhibition by electrophilic agents, compared with HDAC and NF-κB.

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Acknowledgements

We are grateful to J. Oppenheim and J.A. Turpin for critical review of the manuscript; M.R. Anver, H. Zhou and K. Rogers for help with pathology; M.G. Hollingshead and W. Ma for help with animal experiments; and R. Evans and T. Chen for providing plasmids. This project has been funded in whole or in part with Federal funds from the National Cancer Institute and the National Institutes of Health, under Contract NO1-CO-12400.

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Correspondence to Li Hua Wang or William L Farrar.

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Wang, L., Yang, X., Zhang, X. et al. Suppression of breast cancer by chemical modulation of vulnerable zinc fingers in estrogen receptor. Nat Med 10, 40–47 (2004). https://doi.org/10.1038/nm969

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