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[Cancer Research 64, 9199-9208, December 15, 2004]
© 2004 American Association for Cancer Research

Endocrinology

Phosphorylation of Estrogen Receptor {alpha} Blocks Its Acetylation and Regulates Estrogen Sensitivity

Yukun Cui1,2, Mao Zhang2, Richard Pestell4, Edward M. Curran5, Wade V. Welshons6 and Suzanne A. W. Fuqua1,2,3

Departments of 1 Medicine, 2 Breast Center, 3 Molecular and Cellular Biology, Baylor College of Medicine and the Methodist Hospital, Houston, Texas; 4 Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University Medical Center, Washington, District of Columbia; 5 Department of Pediatrics and the Sealy Vaccine Center, University of Texas Medical Branch, Children’s Hospital, Galveston, Texas; and 6 Department of Biomedical Sciences, University of Missouri-Columbia, Columbia, Missouri

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 ER{alpha} is posttranslationally modified by protein acetylation and phosphorylation by a number of secondary messenger signaling cascades. The K303R ER{alpha} 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 ER{alpha} 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 ER{alpha} mutant breast cancer phenotype involves an integration of coupled acetylation and phosphorylation events by upstream signaling molecules.




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