Phosphorylation of estrogen receptor α blocks its acetylation and regulates estrogen sensitivity

Estrogen receptor (ER) alpha is mutated (lysine 303 to arginine, K303R) in approximately one third of premalignant breast hyperplasias, which renders breast cancer cells expressing the mutant receptor hypersensitive for proliferation in response to low doses of estrogen. It is known that ERalpha is...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2004-12, Vol.64 (24), p.9199-9208
Main Authors: YUKUN CUI, MAO ZHANG, PESTELL, Richard, CURRAN, Edward M, WELSHONS, Wade V, FUQUA, Suzanne A. W
Format: Article
Language:English
Subjects:
Acetylation
Antineoplastic agents
Biological and medical sciences
Cell Line, Tumor
Cyclic AMP-Dependent Protein Kinases - metabolism
Estrogen Receptor alpha - antagonists & inhibitors
Estrogen Receptor alpha - metabolism
Estrogens - physiology
Humans
Medical sciences
Pharmacology. Drug treatments
Phenotype
Phosphorylation
Signal Transduction - physiology
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Summary:Estrogen receptor (ER) alpha is mutated (lysine 303 to arginine, K303R) in approximately one third of premalignant breast hyperplasias, which renders breast cancer cells expressing the mutant receptor hypersensitive for proliferation in response to low doses of estrogen. It is known that ERalpha is posttranslationally modified by protein acetylation and phosphorylation by a number of secondary messenger signaling cascades. The K303R ERalpha mutation resides at a major protein acetylation site adjacent to a potential protein kinase A (PKA) phosphorylation site at residue 305 within the hinge domain of the receptor. Mutation of this phosphorylation site to aspartic acid to mimic constitutive phosphorylation blocks acetylation of the K303 ERalpha site and generates an enhanced transcriptional response similar to that seen with the naturally occurring K303R mutant receptor. Activation of PKA signaling by the cell-permeable cyclic AMP (cAMP) analog 8-bromo-cAMP further enhances estrogen sensitivity of the mutant receptor, whereas a specific PKA inhibitor antagonizes this increase. We propose that the hypersensitive ERalpha mutant breast cancer phenotype involves an integration of coupled acetylation and phosphorylation events by upstream signaling molecules.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-04-2126