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

Autor: Alexander Griekspoor, Jacques Neefjes, Astrid Balkenende, Laura van 't Veer, Arno Velds, Rob Michalides, Kees Jalink, Lennert Janssen, Desiree Verwoerd, Arno Floore
Rok vydání: 2004
Předmět:
Cancer Research
Time Factors
Protein Conformation
Estrogen receptor
Pharmacology
Transactivation
Estrogen Receptor Modulators
Fluorescence Resonance Energy Transfer
Serine
polycyclic compounds
Enzyme Inhibitors
Phosphorylation
Luciferases
skin and connective tissue diseases
Fulvestrant
Oligonucleotide Array Sequence Analysis
Microscopy
Confocal
Estradiol
Chemistry
Nucleic Acid Hybridization
Receptors
Estrogen
Oncology
Female
RNA Interference
Cell Division
hormones
hormone substitutes
and hormone antagonists
medicine.drug
Transcriptional Activation
Antineoplastic Agents
Hormonal
Blotting
Western
Down-Regulation
Breast Neoplasms
Transfection
Models
Biological
Downregulation and upregulation
Cell Line
Tumor
medicine
Humans
Protein kinase A
Binding Sites
Estrogen Receptor alpha
Cell Biology
Cyclic AMP-Dependent Protein Kinases
Protein Structure
Tertiary
Enzyme Activation
Tamoxifen
Drug Resistance
Neoplasm
Cancer research
Estrogen receptor alpha
Zdroj: Cancer Cell. 5(6):597-605
ISSN: 1535-6108
DOI: 10.1016/j.ccr.2004.05.016
Popis: 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).
Databáze: OpenAIRE
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