Notch-1 Activates Estrogen Receptor-Alpha-Dependent Transcription via IKKalpha in Breast Cancer Cells

Oncogene. 2010 Jan 14;29(2):201-13. doi: 10.1038/onc.2009.323. Epub 2009 Oct 19.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • E1A-Associated p300 Protein / genetics
  • E1A-Associated p300 Protein / metabolism
  • Estrogen Antagonists / pharmacology
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism
  • Estrogen Receptor alpha / physiology*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • I-kappa B Kinase / genetics*
  • I-kappa B Kinase / metabolism
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / genetics
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / metabolism
  • Mammary Neoplasms, Experimental / drug therapy
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Oligopeptides / pharmacology
  • Promoter Regions, Genetic / genetics
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism
  • Receptor, Notch1 / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tamoxifen / pharmacology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Xenograft Model Antitumor Assays

Substances

  • DNA-Binding Proteins
  • Estrogen Antagonists
  • Estrogen Receptor alpha
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein
  • MAML1 protein, human
  • Oligopeptides
  • RBPJ protein, human
  • Receptor, Notch1
  • Transcription Factors
  • benzyloxycarbonyl-leucyl-leucyl-norleucinal
  • Tamoxifen
  • E1A-Associated p300 Protein
  • EP300 protein, human
  • I-kappa B Kinase