Abstract
Breast tumors expressing estrogen receptor-alpha (ER) respond well to therapeutic strategies using selective ER modulators, such as tamoxifen. However, approximately 30% of invasive breast cancers are hormone independent because they lack ER expression due to hypermethylation of ER promoter. Treatment of ER-negative breast cancer cells with demethylating agents [5-aza-2'-deoxycytidine (5-aza-dC)] and histone deacetylase (HDAC) inhibitors (trichostatin A) leads to expression of ER mRNA and functional protein. Here, we examined whether epigenetically reactivated ER is a target for tamoxifen therapy. Following treatment with trichostatin A and 5-aza-dC, the formerly unresponsive ER-negative MDA-MB-231 breast cancer cells became responsive to tamoxifen. Tamoxifen-mediated inhibition of cell growth in these cells is mediated at least in part by the tamoxifen-bound ER. Tamoxifen-bound reactivated ER induces transcriptional repression at estrogen-responsive genes by ordered recruitment of multiple distinct chromatin-modifying complexes. Using chromatin immunoprecipitation, we show recruitment of two different corepressor complexes to ER-responsive promoters in a mutually exclusive and sequential manner: the nuclear receptor corepressor-HDAC3 complex followed by nucleosome remodeling and histone deacetylation complex. The mechanistic insight provided by this study might help in designing therapeutic strategies directed toward epigenetic mechanisms in the prevention or treatment of breast cancer.
Publication types
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Research Support, N.I.H., Extramural
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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 Combined Chemotherapy Protocols / pharmacology
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Azacitidine / administration & dosage
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Azacitidine / analogs & derivatives
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Azacitidine / pharmacology
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Cell Line, Tumor
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DNA (Cytosine-5-)-Methyltransferases / antagonists & inhibitors
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DNA (Cytosine-5-)-Methyltransferases / metabolism
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Decitabine
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Drug Synergism
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Estrogen Antagonists / administration & dosage
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Estrogen Antagonists / metabolism
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Estrogen Antagonists / pharmacology*
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Estrogen Receptor alpha / biosynthesis
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Estrogen Receptor alpha / genetics
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Estrogen Receptor alpha / metabolism*
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Histone Deacetylase Inhibitors
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism
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Humans
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Hydroxamic Acids / administration & dosage
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Hydroxamic Acids / pharmacology
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Mi-2 Nucleosome Remodeling and Deacetylase Complex
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Promoter Regions, Genetic
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Sin3 Histone Deacetylase and Corepressor Complex
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Tamoxifen / administration & dosage
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Tamoxifen / metabolism
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Tamoxifen / pharmacology*
Substances
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Estrogen Antagonists
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Estrogen Receptor alpha
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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RNA, Messenger
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Repressor Proteins
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SIN3A transcription factor
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Tamoxifen
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trichostatin A
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Decitabine
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DNA (Cytosine-5-)-Methyltransferases
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Histone Deacetylases
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Mi-2 Nucleosome Remodeling and Deacetylase Complex
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Sin3 Histone Deacetylase and Corepressor Complex
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Azacitidine