Notch-1 activates estrogen receptor-alpha-dependent transcription via IKKalpha in breast cancer cells.
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.
Mesh Terms:
Animals, Blotting, Western, Breast Neoplasms, Cell Line, Tumor, DNA-Binding Proteins, E1A-Associated p300 Protein, Estrogen Antagonists, Estrogen Receptor alpha, Female, Gene Expression Regulation, Neoplastic, Humans, I-kappa B Kinase, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Mammary Neoplasms, Experimental, Mice, Mice, Inbred BALB C, Mice, Nude, Oligopeptides, Promoter Regions, Genetic, Receptor, Notch1, Reverse Transcriptase Polymerase Chain Reaction, Tamoxifen, Transcription Factors, Transcription, Genetic, Xenograft Model Antitumor Assays
Animals, Blotting, Western, Breast Neoplasms, Cell Line, Tumor, DNA-Binding Proteins, E1A-Associated p300 Protein, Estrogen Antagonists, Estrogen Receptor alpha, Female, Gene Expression Regulation, Neoplastic, Humans, I-kappa B Kinase, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Mammary Neoplasms, Experimental, Mice, Mice, Inbred BALB C, Mice, Nude, Oligopeptides, Promoter Regions, Genetic, Receptor, Notch1, Reverse Transcriptase Polymerase Chain Reaction, Tamoxifen, Transcription Factors, Transcription, Genetic, Xenograft Model Antitumor Assays
Oncogene
Date: Jan. 14, 2010
PubMed ID: 19838210
View in: Pubmed Google Scholar
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