Abstract
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.
Highlights
Estrogen receptor (ER) ␣ is a member of a large family of nuclear steroid receptors that function as transcription factors mediating the mitogenic effects of estrogen
Because prolonged estrogen exposure is a known risk factor for developing invasive breast cancer [1], we hypothesized that the emergence of a mutated receptor could be an early event occurring in premalignant breast disease, and we subsequently identified a lysine to arginine somatic mutation at residue 303 (K303R) in ER␣ from human ductal hyperplasias that conferred increased responsiveness to subphysiologic levels of hormone [2]
Because an A to G transition (K303R) at ER␣ K303 was the only change ever found in premalignant breast lesions [2], we hypothesized that this specific residue alteration might be biologically relevant and provide an altered hormone response to cells
Summary
Estrogen receptor (ER) ␣ is a member of a large family of nuclear steroid receptors that function as transcription factors mediating the mitogenic effects of estrogen. ER-positive MCF-7 breast cancer cells can gradually adjust to long-term estrogen deprivation, resulting in a phenotype that has been termed adaptive hypersensitivity [29], with concomitant up-regulation of growth factor receptors [30] and/or activation of downstream signaling molecules such as extracellular signal-regulated kinases 1/2 and AKT (30 –32). These studies led us to question whether activation of specific signaling molecules might be involved in the hypersensitive phenotype associated with the K303R ER␣ mutation
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