Disruption of estrogen receptor DNA-binding domain and related intramolecular communication restores tamoxifen sensitivity in resistant breast cancer

Cancer Cell. 2006 Dec;10(6):487-99. doi: 10.1016/j.ccr.2006.09.015.


A serious obstacle to successful treatment of estrogen receptor (ER)-positive human breast cancer is cell resistance to tamoxifen (TAM) therapy. Here we show that the electrophile disulfide benzamide (DIBA), an ER zinc finger inhibitor, blocks ligand-dependent and -independent cell growth of TAM-resistant breast cancer in vitro and in vivo. Such inhibition depends on targeting disruption of the ER DNA-binding domain and its communication with neighboring functional domains, facilitating ERalpha dissociation from its coactivator AIB1 and concomitant association with its corepressor NCoR bound to chromatin. DIBA does not affect phosphorylation of HER2, MAPK, AKT, and AIB1, suggesting that DIBA-modified ERalpha may induce a switch from agonistic to antagonistic effects of TAM on resistant breast cancer cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Antineoplastic Agents, Hormonal / pharmacology*
  • Benzamides / pharmacology*
  • Binding Sites
  • Breast Neoplasms / drug therapy*
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • DNA / metabolism*
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Estrogen Receptor alpha / chemistry
  • Estrogen Receptor alpha / metabolism
  • Estrogen Receptor alpha / physiology*
  • Female
  • Humans
  • Mice
  • Phosphorylation
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, ErbB-2 / metabolism
  • Response Elements
  • Tamoxifen / pharmacology*


  • Antineoplastic Agents, Hormonal
  • Benzamides
  • Estrogen Receptor alpha
  • Tamoxifen
  • benzamide
  • DNA
  • Receptor, ErbB-2
  • Proto-Oncogene Proteins c-akt