Abstract
Many cofactors bind the hormone-activated estrogen receptor (ER), yet the specific regulators of endogenous ER-mediated gene transcription are unknown. Using chromatin immunoprecipitation (ChIP), we find that ER and a number of coactivators rapidly associate with estrogen responsive promoters following estrogen treatment in a cyclic fashion that is not predicted by current models of hormone activation. Cycles of ER complex assembly are followed by transcription. In contrast, the anti-estrogen tamoxifen (TAM) recruits corepressors but not coactivators. Using a genetic approach, we show that recruitment of the p160 class of coactivators is sufficient for gene activation and for the growth stimulatory actions of estrogen in breast cancer supporting a model in which ER cofactors play unique roles in estrogen signaling.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Breast Neoplasms
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Cathepsin D / genetics
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Cathepsin D / metabolism
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Chromatin / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Estradiol / pharmacology*
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Estrogen Receptor alpha
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Female
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Gene Expression Regulation / drug effects*
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Histones / chemistry
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Humans
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Macromolecular Substances
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Nuclear Receptor Coactivator 2
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Nuclear Receptor Coactivator 3
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Precipitin Tests
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Promoter Regions, Genetic / genetics*
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Proteins / genetics
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Proteins / metabolism
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Receptors, Estrogen / genetics
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Receptors, Estrogen / metabolism*
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Signal Transduction
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Tamoxifen / pharmacology*
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcriptional Activation*
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Trefoil Factor-1
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Tumor Cells, Cultured
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Tumor Suppressor Proteins
Substances
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Chromatin
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DNA-Binding Proteins
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Estrogen Receptor alpha
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Histones
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Macromolecular Substances
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NCOA2 protein, human
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Nuclear Receptor Coactivator 2
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Proteins
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Receptors, Estrogen
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TFF1 protein, human
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Transcription Factors
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Trefoil Factor-1
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Tumor Suppressor Proteins
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Tamoxifen
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Estradiol
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Nuclear Receptor Coactivator 3
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Cathepsin D