Document Detail


Dose-dependent induction of distinct phenotypic responses to Notch pathway activation in mammary epithelial cells.
MedLine Citation:
PMID:  20194747     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Aberrant activation of Notch receptors has been implicated in breast cancer; however, the mechanisms contributing to Notch-dependent transformation remain elusive because Notch displays dichotomous functional activities, promoting both proliferation and growth arrest. We investigated the cellular basis for the heterogeneous responses to Notch pathway activation in 3D cultures of MCF-10A mammary epithelial cells. Expression of a constitutively active Notch-1 intracellular domain (NICD) was found to induce two distinct types of 3D structures: large, hyperproliferative structures and small, growth-arrested structures with reduced cell-to-matrix adhesion. Interestingly, we found that these heterogeneous phenotypes reflect differences in Notch pathway activation levels; high Notch activity caused down-regulation of multiple matrix-adhesion genes and inhibition of proliferation, whereas low Notch activity maintained matrix adhesion and provoked a strong hyperproliferative response. Moreover, microarray analyses implicated NICD-induced p63 down-regulation in loss of matrix adhesion. In addition, a reverse-phase protein array-based analysis and subsequent loss-of-function studies identified STAT3 as a dominant downstream mediator of the NICD-induced outgrowth. These results indicate that the phenotypic responses to Notch are determined by the dose of pathway activation; and this dose affects the balance between growth-stimulative and growth-suppressive effects. This unique feature of Notch signaling provides insights into mechanisms that contribute to the dichotomous effects of Notch during development and tumorigenesis.
Authors:
Marco Mazzone; Laura M Selfors; John Albeck; Michael Overholtzer; Sanja Sale; Danielle L Carroll; Darshan Pandya; Yiling Lu; Gordon B Mills; Jon C Aster; Spyros Artavanis-Tsakonas; Joan S Brugge
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2010-03-01
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  107     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2010 Mar 
Date Detail:
Created Date:  2010-03-22     Completed Date:  2010-04-22     Revised Date:  2014-09-12    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5012-7     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Cell Adhesion
Cell Proliferation
Cells, Cultured
Epithelial Cells / cytology,  metabolism*
Extracellular Matrix / metabolism
Female
Humans
Mammary Glands, Human / cytology*
Phenotype
Protein Structure, Tertiary
Receptor, Notch1 / chemistry,  metabolism*
STAT3 Transcription Factor / metabolism
Signal Transduction*
Trans-Activators / metabolism
Transcription Factors
Tumor Suppressor Proteins / metabolism
Grant Support
ID/Acronym/Agency:
P01 CA099031/CA/NCI NIH HHS; P01 CA105134/CA/NCI NIH HHS; P01 CA119070/CA/NCI NIH HHS; P30CA16672/CA/NCI NIH HHS; R01 CA098402/CA/NCI NIH HHS; R01 CA098402/CA/NCI NIH HHS; R37 NS26084/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/NOTCH1 protein, human; 0/Receptor, Notch1; 0/STAT3 Transcription Factor; 0/STAT3 protein, human; 0/TP63 protein, human; 0/Trans-Activators; 0/Transcription Factors; 0/Tumor Suppressor Proteins
Comments/Corrections

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