Tamoxifen resistance by a conformational arrest of the estrogen receptor alpha after PKA activation in breast cancer

Cancer Cell. 2004 Jun;5(6):597-605. doi: 10.1016/j.ccr.2004.05.016.


Using a novel approach that detects changes in the conformation of ERalpha, we studied the efficacy of anti-estrogens to inactivate ERalpha under different experimental conditions. We show that phosphorylation of serine-305 in the hinge region of ERalpha by protein kinase A (PKA) induced resistance to tamoxifen. Tamoxifen bound but then failed to induce the inactive conformation, invoking ERalpha-dependent transactivation instead. PKA activity thus induces a switch from antagonistic to agonistic effects of tamoxifen on ERalpha. In clinical samples, we found that downregulation of a negative regulator of PKA, PKA-RIalpha, was associated with tamoxifen resistance prior to treatment. Activation of PKA by downregulation of PKA-RIalpha converts tamoxifen from an ERalpha inhibitor into a growth stimulator, without any effect on ICI 182780 (Fulvestrant).

MeSH terms

  • Antineoplastic Agents, Hormonal / pharmacology
  • Binding Sites
  • Blotting, Western
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / pathology*
  • Cell Division
  • Cell Line, Tumor
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Down-Regulation
  • Drug Resistance, Neoplasm*
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Estradiol / analogs & derivatives*
  • Estradiol / pharmacology
  • Estrogen Receptor Modulators / pharmacology
  • Estrogen Receptor alpha
  • Female
  • Fluorescence Resonance Energy Transfer
  • Fulvestrant
  • Humans
  • Luciferases / metabolism
  • Microscopy, Confocal
  • Models, Biological
  • Nucleic Acid Hybridization
  • Oligonucleotide Array Sequence Analysis
  • Phosphorylation
  • Protein Conformation
  • Protein Structure, Tertiary
  • RNA Interference
  • Receptors, Estrogen / chemistry*
  • Receptors, Estrogen / metabolism
  • Serine / chemistry
  • Tamoxifen / pharmacology*
  • Time Factors
  • Transcriptional Activation
  • Transfection


  • Antineoplastic Agents, Hormonal
  • Enzyme Inhibitors
  • Estrogen Receptor Modulators
  • Estrogen Receptor alpha
  • Receptors, Estrogen
  • Tamoxifen
  • Fulvestrant
  • Serine
  • Estradiol
  • Luciferases
  • Cyclic AMP-Dependent Protein Kinases