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PMID: 19838210 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Notch-1 activates estrogen receptor-alpha-dependent transcription via IKKalpha in breast cancer cells.

Oncogene ·Vol. 29 ·No. 2 ·2010-01-14 ·Pages 201-13

Hao L, Rizzo P, Osipo C, Pannuti A, Wyatt D, Cheung LW, Sonenshein G, Osborne BA, Miele L

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.

MeSH Terms
Animals Blotting, Western Breast Neoplasms/genetics,metabolism,pathology Cell Line, Tumor DNA-Binding Proteins/genetics,metabolism E1A-Associated p300 Protein/genetics,metabolism Estrogen Antagonists/pharmacology Estrogen Receptor alpha/genetics,metabolism,physiology Female Gene Expression Regulation, Neoplastic Humans I-kappa B Kinase/genetics,metabolism Immunoglobulin J Recombination Signal Sequence-Binding Protein/genetics,metabolism Mammary Neoplasms, Experimental/drug therapy,genetics,pathology Mice Mice, Inbred BALB C Mice, Nude Oligopeptides/pharmacology Promoter Regions, Genetic/genetics Receptor, Notch1/genetics,metabolism,physiology Reverse Transcriptase Polymerase Chain Reaction Tamoxifen/pharmacology Transcription Factors/genetics,metabolism Transcription, Genetic Xenograft Model Antitumor Assays
Chemicals
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
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Hao L
Breast Cancer Program, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL, USA.
Rizzo P
Osipo C
Pannuti A
Wyatt D
Cheung L W-K
Sonenshein G
Osborne B A
Miele L
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Article Info
Journal
Oncogene
Abbr.
Oncogene
ISSN
1476-5594
DOI
10.1038/onc.2009.323
Published
2010-01-14
Epub
2009-00-19
Pages
201-13
Language
English
Region
England
NLM ID
8711562
PMCID
PMC4976641
Subset
IM
Grants
NIA NIH HHS · P01 AG025531 · United States
NIA NIH HHS · P01AG025531 · United States
External Links
PubMed source DOI: 10.1038/onc.2009.323 PMC Full Text View journal details
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