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Suppression of breast cancer by chemical modulation of vulnerable zinc fingers in estrogen receptor
- Source :
- Nature medicine. 10(1)
- Publication Year :
- 2003
-
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.
- Subjects :
- Transcriptional Activation
medicine.medical_specialty
Antineoplastic Agents, Hormonal
medicine.drug_class
Estrogen receptor
Apoptosis
Breast Neoplasms
General Biochemistry, Genetics and Molecular Biology
Breast cancer
Estrogen Receptor Modulators
Internal medicine
Cell Line, Tumor
medicine
Humans
Estrogen binding
skin and connective tissue diseases
DNA Primers
Zinc finger
Base Sequence
business.industry
Cell growth
Cell Cycle
Zinc Fingers
General Medicine
DNA, Neoplasm
medicine.disease
Thiazoles
Endocrinology
Selective estrogen receptor modulator
Estrogen
Benzamides
Cancer research
Breast carcinoma
business
hormones, hormone substitutes, and hormone antagonists
Subjects
Details
- ISSN :
- 10788956
- Volume :
- 10
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Nature medicine
- Accession number :
- edsair.doi.dedup.....6913aebc7d390f6c2f7c79703813bfe6