Hypoxia induces proteasome-dependent degradation of estrogen receptor alpha in ZR-75 breast cancer cells

Mol Endocrinol. 2002 Oct;16(10):2231-42. doi: 10.1210/me.2001-0347.

Abstract

Regulation of estrogen receptor alpha (ERalpha) plays an important role in hormone responsiveness and growth of ER-positive breast cancer cells and tumors. ZR-75 breast cancer cells were grown under conditions of normoxia (21% O(2)) or hypoxia (1% O(2) or cobaltous chloride), and hypoxia significantly increased hypoxia-inducible factor 1alpha protein within 3 h after treatment, whereas ERalpha protein levels were dramatically decreased within 6-12 h, and this response was blocked by the proteasome inhibitor MG-132. In contrast, hypoxia induced only minimal decreases in cellular Sp1 protein and did not affect ERalpha mRNA; however, hypoxic conditions decreased basal and 17beta-estradiol-induced pS2 gene expression (mRNA levels) and estrogen response element-dependent reporter gene activity in ZR-75 cells. Although 17beta-estradiol and hypoxia induce proteasome-dependent degradation of ERalpha, their effects on transactivation are different, and this may have implications for clinical treatment of mammary tumors.

Publication types

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

MeSH terms

  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Division / drug effects
  • Cell Hypoxia
  • Cobalt / pharmacology
  • Cysteine Endopeptidases / metabolism*
  • Endothelial Growth Factors / genetics
  • Estradiol / pharmacology
  • Estrogen Receptor alpha
  • Female
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Intercellular Signaling Peptides and Proteins / genetics
  • Leupeptins / pharmacology
  • Lymphokines / genetics
  • Multienzyme Complexes / antagonists & inhibitors
  • Multienzyme Complexes / metabolism*
  • Promoter Regions, Genetic
  • Protease Inhibitors / pharmacology
  • Proteasome Endopeptidase Complex
  • Proteins / drug effects
  • Proteins / genetics
  • Receptors, Estrogen / drug effects
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism*
  • Response Elements / drug effects
  • Response Elements / genetics
  • Sp1 Transcription Factor / drug effects
  • Sp1 Transcription Factor / metabolism
  • Transcription Factors / drug effects
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcriptional Activation
  • Trefoil Factor-1
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors

Substances

  • Endothelial Growth Factors
  • Estrogen Receptor alpha
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Intercellular Signaling Peptides and Proteins
  • Leupeptins
  • Lymphokines
  • Multienzyme Complexes
  • Protease Inhibitors
  • Proteins
  • Receptors, Estrogen
  • Sp1 Transcription Factor
  • TFF1 protein, human
  • Transcription Factors
  • Trefoil Factor-1
  • Tumor Suppressor Proteins
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Cobalt
  • Estradiol
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • cobaltous chloride
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde