Abstract
Approximately 80% of breast cancers express the estrogen receptor-alpha (ERalpha) and are treated with anti-estrogens. Resistance to these agents is a major cause of mortality. We have shown that estrogen inhibits Notch, whereas anti-estrogens or estrogen withdrawal activate Notch signaling. Combined inhibition of Notch and estrogen signaling has synergistic effects in ERalpha-positive breast cancer models. However, the mechanisms whereby Notch-1 promotes the growth of ERalpha-positive breast cancer cells are unknown. Here, we demonstrate that Notch-1 increases the transcription of ERalpha-responsive genes in the presence or absence of estrogen via a novel chromatin crosstalk mechanism. Our data support a model in which Notch-1 can activate the transcription of ERalpha-target genes via IKKalpha-dependent cooperative chromatin recruitment of Notch-CSL-MAML1 transcriptional complexes (NTC) and ERalpha, which promotes the recruitment of p300. CSL binding elements frequently occur in close proximity to estrogen-responsive elements (EREs) in the human and mouse genomes. Our observations suggest that a hitherto unknown Notch-1/ERalpha chromatin crosstalk mediates Notch signaling effects in ERalpha-positive breast cancer cells and contributes to regulate the transcriptional functions of ERalpha itself.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Breast Neoplasms / genetics*
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Cell Line, Tumor
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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E1A-Associated p300 Protein / genetics
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E1A-Associated p300 Protein / metabolism
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Estrogen Antagonists / pharmacology
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Estrogen Receptor alpha / genetics
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Estrogen Receptor alpha / metabolism
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Estrogen Receptor alpha / physiology*
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Female
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Gene Expression Regulation, Neoplastic
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Humans
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I-kappa B Kinase / genetics*
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I-kappa B Kinase / metabolism
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Immunoglobulin J Recombination Signal Sequence-Binding Protein / genetics
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Immunoglobulin J Recombination Signal Sequence-Binding Protein / metabolism
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Mammary Neoplasms, Experimental / drug therapy
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Mammary Neoplasms, Experimental / genetics
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Mammary Neoplasms, Experimental / pathology
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Oligopeptides / pharmacology
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Promoter Regions, Genetic / genetics
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Receptor, Notch1 / genetics
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Receptor, Notch1 / metabolism
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Receptor, Notch1 / physiology*
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Reverse Transcriptase Polymerase Chain Reaction
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Tamoxifen / pharmacology
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription, Genetic
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Xenograft Model Antitumor Assays
Substances
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DNA-Binding Proteins
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Estrogen Antagonists
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Estrogen Receptor alpha
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Immunoglobulin J Recombination Signal Sequence-Binding Protein
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MAML1 protein, human
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Oligopeptides
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RBPJ protein, human
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Receptor, Notch1
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Transcription Factors
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benzyloxycarbonyl-leucyl-leucyl-norleucinal
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Tamoxifen
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E1A-Associated p300 Protein
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EP300 protein, human
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I-kappa B Kinase