Dose-dependent induction of distinct phenotypic responses to Notch pathway activation in mammary epithelial cells Journal Article
| Authors: | Mazzone, M.; Selfors, L. M.; Albeck, J.; Overholtzer, M.; Sale, S.; Carroll, D. L.; Pandya, D.; Lu, Y.; Mills, G. B.; Aster, J. C.; Artavanis-Tsakonas, S.; Brugge, J. S. |
| Article Title: | Dose-dependent induction of distinct phenotypic responses to Notch pathway activation in mammary epithelial cells |
| Abstract: | 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. |
| Keywords: | signal transduction; controlled study; protein expression; human cell; protein domain; cell proliferation; phenotype; cells, cultured; cell structure; stat3 protein; gene expression profiling; cell growth; breast; protein depletion; cell line; notch receptor; morphogenesis; receptor, notch1; extracellular matrix; cell culture; microarray analysis; cell transformation; nucleotide sequence; tumor suppressor proteins; breast epithelium; protein induction; epithelial cells; cell cycle arrest; cellular distribution; stat3 transcription factor; protein structure, tertiary; protein p63; trans-activators; cell adhesion; loss of function mutation; protein microarray; notch1 receptor; mammary glands, human; transformation; growth inhibition; adhesion; mediator; matrix; receptor down regulation; reversed phase liquid chromatography |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 107 |
| Issue: | 11 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2010-03-16 |
| Start Page: | 5012 |
| End Page: | 5017 |
| Language: | English |
| DOI: | 10.1073/pnas.1000896107 |
| PUBMED: | 20194747 |
| PROVIDER: | scopus |
| PMCID: | PMC2841923 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 6" - "Export Date: 20 April 2011" - "CODEN: PNASA" - "Source: Scopus" |
