Suppression of Breast Cancer by Chemical Modulation of Vulnerable Zinc Fingers in Estrogen Receptor

Nat Med. 2004 Jan;10(1):40-7. doi: 10.1038/nm969. Epub 2003 Dec 14.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents, Hormonal / therapeutic use*
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Base Sequence
  • Benzamides / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Cell Cycle / drug effects
  • Cell Cycle / genetics
  • Cell Line, Tumor
  • DNA Primers
  • DNA, Neoplasm / metabolism
  • Estrogen Receptor Modulators / therapeutic use*
  • Humans
  • Thiazoles / therapeutic use*
  • Transcriptional Activation
  • Zinc Fingers*

Substances

  • Antineoplastic Agents, Hormonal
  • Benzamides
  • DNA Primers
  • DNA, Neoplasm
  • Estrogen Receptor Modulators
  • Thiazoles
  • benzisothiazole
  • benzamide

Associated data

  • PDB/1A6Y
  • PDB/1GDC
  • PDB/1GLU
  • PDB/1HCP
  • PDB/1HCQ
  • PDB/1HRA
  • PDB/1LAT
  • PDB/1RXR
  • PDB/2NLL