Abstract
Estrogen receptor alpha (ERalpha) mediates the effects of estrogens in breast cancer development and growth via transcriptional regulation of target genes. Tamoxifen can antagonize ERalpha activity and has been used in breast cancer therapy. Tamoxifen-bound ERalpha associates with nuclear receptor corepressor (N-CoR) and silencing mediator for retinoid and thyroid hormone receptors (SMRT) at certain target genes. Here we show the effects of reducing N-CoR and SMRT levels on the actions of estrogen and tamoxifen in breast cancer cells. Silencing both corepressors led to tamoxifen-stimulated cell cycle progression without activation of the ERalpha target genes c-myc, cyclin D1, or stromal cell-derived factor 1, which play a role in estrogen-induced proliferation. By contrast, expression of X-box binding protein 1 was markedly elevated in tamoxifen-treated cells in which N-CoR and SMRT had been silenced. The gain in cell cycle entry seen with tamoxifen when N-CoR and SMRT were silenced was dependent on ERalpha and not observed upon treatment with estradiol or epidermal growth factor. These results suggest that N-CoR and SMRT play an active role in preventing tamoxifen from stimulating proliferation in breast cancer cells through repression of a subset of target genes involved in ERalpha function and cell proliferation.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Antineoplastic Agents, Hormonal / pharmacology*
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Breast Neoplasms / metabolism
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Cell Cycle
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Cell Line, Tumor
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Cell Proliferation
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology*
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Dose-Response Relationship, Drug
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Estradiol / metabolism
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Estrogen Receptor alpha / metabolism*
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Gene Silencing
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Humans
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Immunoblotting
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Luciferases / metabolism
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Nuclear Proteins / metabolism
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Nuclear Proteins / physiology*
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Nuclear Receptor Co-Repressor 1
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Nuclear Receptor Co-Repressor 2
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Promoter Regions, Genetic
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Protein Binding
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RNA Interference
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RNA, Small Interfering / metabolism
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Regulatory Factor X Transcription Factors
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Repressor Proteins / physiology*
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Reverse Transcriptase Polymerase Chain Reaction
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Tamoxifen / chemistry
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Tamoxifen / pharmacology*
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Time Factors
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Transcription Factors
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Transcription, Genetic
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Transcriptional Activation
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Transfection
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beta-Galactosidase / metabolism
Substances
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Antineoplastic Agents, Hormonal
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DNA-Binding Proteins
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Estrogen Receptor alpha
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NCOR1 protein, human
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NCOR2 protein, human
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Nuclear Proteins
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Nuclear Receptor Co-Repressor 1
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Nuclear Receptor Co-Repressor 2
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RNA, Small Interfering
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Regulatory Factor X Transcription Factors
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Repressor Proteins
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Transcription Factors
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Tamoxifen
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Estradiol
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Luciferases
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beta-Galactosidase