Hypoxia and estrogen receptor profile influence the responsiveness of human breast cancer cells to estradiol and antiestrogens

Cell Mol Life Sci. 2004 Jan;61(1):76-82. doi: 10.1007/s00018-003-3324-0.


Angiogenesis activation mediated by vascular endothelial growth factor (VEGF) is one of the factors that can cause antiestrogen treatment failure in estrogen receptor (ER)?positive breast cancer patients. Since VEGF synthesis is modulated not only by hypoxia but also by steroid hormones, we investigated the relationship between hypoxic and estrogenic/antiestrogenic stimuli in two human breast cancer cell lines expressing both ER6alpha and ERbeta (MCF7) or only ERbeta (MDA-MB231). In both cell lines, the VEGF level was significantly influenced by hypoxic conditions and in antiestrogen-responsive MCF7 cells, this effect was not counteracted by tamoxifen or ICI 182780, thus providing an experimental explanation for the resistance to endocrine treatment observed in patients with ER-positive tumors. In MDA-MB231 cells, estradiol significantly reduced the VEGF level, suggesting that through the ERbeta isoform it may function as a negative modulator of VEGF synthesis under hypoxia, and providing evidence for a complex interplay of the estrogen-dependent and hypoxia-dependent pathways.

MeSH terms

  • Antineoplastic Agents, Hormonal / pharmacology
  • Breast Neoplasms
  • Cell Hypoxia / drug effects
  • Cell Hypoxia / physiology*
  • Cobalt / pharmacology
  • Estradiol / pharmacology*
  • Estrogen Receptor Modulators / pharmacology*
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Female
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Receptors, Estrogen / drug effects
  • Receptors, Estrogen / physiology*
  • Tamoxifen / analogs & derivatives*
  • Tamoxifen / pharmacology
  • Transcription Factors / metabolism
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A / metabolism


  • Antineoplastic Agents, Hormonal
  • Estrogen Receptor Modulators
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Receptors, Estrogen
  • Transcription Factors
  • Vascular Endothelial Growth Factor A
  • Tamoxifen
  • afimoxifene
  • Cobalt
  • Estradiol
  • cobaltous chloride