Ligand-independent and agonist-mediated degradation of estrogen receptor-alpha in breast carcinoma cells: evidence for distinct degradative pathways

Mol Cell Endocrinol. 2004 Nov 30;227(1-2):53-65. doi: 10.1016/j.mce.2004.07.003.

Abstract

Molecular chaperones and co-chaperones, such as heat-shock proteins (Hsp's), play a pivotal role in the adequate folding and the stability of steroid hormone receptors. As shown by immunofluorescence staining and immunoblot analysis, the Hsp90 inhibitor radicicol induced a rapid (within hours) depletion of estrogen receptor-alpha (ER) in MCF-7 and IBEP-2 breast carcinoma cells. Inhibition of proteasomes (MG-132, LLnL) or of protein synthesis (cycloheximide), which both suppressed E(2)-induced downregulation of ER, failed to modify ER degradation caused by radicicol. On the other hand, partial antiestrogens, such as hydroxytamoxifen (a triphenylethylene) and LY 117,018 (a benzothiophene) stabilized ER, making it immune to radicicol-induced degradation. Furthermore, radicicol did not interfere with ER upregulation induced by hydroxytamoxifen. Thus, the current study points to possible variation in the mechanism/pathway of ER breakdown. Besides, the protective effect of partial antiestrogens suggests that ER stability is only compromized by Hsp90 disruption when the receptor is in its native, unliganded form.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / metabolism*
  • Cycloheximide / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Estrogen Antagonists / pharmacology*
  • Estrogen Receptor alpha / drug effects
  • Estrogen Receptor alpha / metabolism*
  • Female
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Neoplastic*
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Immunoenzyme Techniques
  • Lactones / pharmacology
  • Leupeptins / pharmacology
  • Ligands
  • Macrolides
  • Molecular Chaperones / metabolism
  • Proteasome Inhibitors
  • Protein Synthesis Inhibitors / pharmacology
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Pyrrolidines / pharmacology
  • Signal Transduction*
  • Tamoxifen / analogs & derivatives*
  • Tamoxifen / pharmacology
  • Thiophenes / pharmacology
  • Tumor Cells, Cultured

Substances

  • Enzyme Inhibitors
  • Estrogen Antagonists
  • Estrogen Receptor alpha
  • HSP90 Heat-Shock Proteins
  • Lactones
  • Leupeptins
  • Ligands
  • Macrolides
  • Molecular Chaperones
  • Proteasome Inhibitors
  • Protein Synthesis Inhibitors
  • Pyrrolidines
  • Thiophenes
  • Tamoxifen
  • afimoxifene
  • LY 117018
  • Cycloheximide
  • Protein-Tyrosine Kinases
  • monorden
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde