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PMID:16501043

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Citation

Ayyanan, A, Civenni, G, Ciarloni, L, Morel, C, Mueller, N, Lefort, K, Mandinova, A, Raffoul, W, Fiche, M, Dotto, GP and Brisken, C (2006) Increased Wnt signaling triggers oncogenic conversion of human breast epithelial cells by a Notch-dependent mechanism. Proc. Natl. Acad. Sci. U.S.A. 103:3799-804

Abstract

Wnt and Notch signaling have long been established as strongly oncogenic in the mouse mammary gland. Aberrant expression of several Wnts and other components of this pathway in human breast carcinomas has been reported, but evidence for a causative role in the human disease has been missing. Here we report that increased Wnt signaling, as achieved by ectopic expression of Wnt-1, triggers the DNA damage response (DDR) and an ensuing cascade of events resulting in tumorigenic conversion of primary human mammary epithelial cells. Wnt-1-transformed cells have high telomerase activity and compromised p53 and Rb function, grow as spheres in suspension, and in mice form tumors that closely resemble medullary carcinomas of the breast. Notch signaling is up-regulated through a mechanism involving increased expression of the Notch ligands Dll1, Dll3, and Dll4 and is required for expression of the tumorigenic phenotype. Increased Notch signaling in primary human mammary epithelial cells is sufficient to reproduce some aspects of Wnt-induced transformation. The relevance of these findings for human breast cancer is supported by the fact that expression of Wnt-1 and Wnt-4 and of established Wnt target genes, such as Axin-2 and Lef-1, as well as the Notch ligands, such as Dll3 and Dll4, is up-regulated in human breast carcinomas.

Links

PubMed PMC1450156 Online version:10.1073/pnas.0600065103

Keywords

Animals; Breast/cytology; Breast/metabolism; Breast Neoplasms/etiology; Breast Neoplasms/metabolism; Breast Neoplasms/pathology; Cell Transformation, Neoplastic/genetics; Cell Transformation, Neoplastic/metabolism; Cell Transformation, Neoplastic/pathology; Cells, Cultured; DNA Damage; Epithelial Cells/metabolism; Female; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; RNA, Messenger/genetics; RNA, Messenger/metabolism; RNA, Neoplasm/genetics; RNA, Neoplasm/metabolism; Receptors, Notch/metabolism; Signal Transduction; Wnt1 Protein/genetics; Wnt1 Protein/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:WNT1

involved_in

GO:0008284: positive regulation of cell population proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:WNT1

involved_in

GO:0010812: negative regulation of cell-substrate adhesion

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:WNT1

involved_in

GO:0042770: signal transduction in response to DNA damage

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:WNT1

involved_in

GO:0045747: positive regulation of Notch signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:WNT1

involved_in

GO:0090344: negative regulation of cell aging

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NOTC1

involved_in

GO:0010812: negative regulation of cell-substrate adhesion

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


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References

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Internal error

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[d926406e240cd78ccf859302] /wiki/index.php/PMID:16501043 Error from line 252 of /usr/local/github/wiki-extensions/wiki-extensions-hulab/AnnotationLinks/AnnotationLinks.php: Call to a member function getIdentifier() on null

Backtrace:

#0 /usr/local/github/wiki-extensions/wiki-extensions-hulab/AnnotationLinks/AnnotationLinks.php(70): AnnotationLinks::getQuickGOannotations(string, array)
#1 /var/www/html/go/wiki/includes/parser/Parser.php(3888): AnnotationLinks::renderAnnotations(NULL, array, Parser, PPFrame_DOM)
#2 /var/www/html/go/wiki/includes/parser/Preprocessor_DOM.php(1362): Parser->extensionSubstitution(array, PPFrame_DOM)
#3 /var/www/html/go/wiki/includes/parser/Parser.php(2942): PPFrame_DOM->expand(DOMElement, integer)
#4 /var/www/html/go/wiki/includes/parser/Parser.php(1293): Parser->replaceVariables(string)
#5 /var/www/html/go/wiki/includes/parser/Parser.php(443): Parser->internalParse(string)
#6 /var/www/html/go/wiki/includes/content/WikitextContent.php(323): Parser->parse(string, Title, ParserOptions, boolean, boolean, integer)
#7 /var/www/html/go/wiki/includes/content/AbstractContent.php(516): WikitextContent->fillParserOutput(Title, integer, ParserOptions, boolean, ParserOutput)
#8 /var/www/html/go/wiki/includes/jobqueue/jobs/RefreshLinksJob.php(231): AbstractContent->getParserOutput(Title, integer, ParserOptions, boolean)
#9 /var/www/html/go/wiki/includes/jobqueue/jobs/RefreshLinksJob.php(126): RefreshLinksJob->runForTitle(Title)
#10 /var/www/html/go/wiki/includes/jobqueue/JobRunner.php(296): RefreshLinksJob->run()
#11 /var/www/html/go/wiki/includes/jobqueue/JobRunner.php(193): JobRunner->executeJob(RefreshLinksJob, Wikimedia\Rdbms\LBFactorySimple, BufferingStatsdDataFactory, integer)
#12 /var/www/html/go/wiki/includes/MediaWiki.php(1002): JobRunner->run(array)
#13 /var/www/html/go/wiki/includes/MediaWiki.php(988): MediaWiki->triggerSyncJobs(integer, MediaWiki\Logger\LegacyLogger)
#14 /var/www/html/go/wiki/includes/MediaWiki.php(912): MediaWiki->triggerJobs()
#15 /var/www/html/go/wiki/includes/MediaWiki.php(727): MediaWiki->restInPeace(string, boolean)
#16 /var/www/html/go/wiki/includes/MediaWiki.php(750): MediaWiki->{closure}()
#17 /var/www/html/go/wiki/includes/MediaWiki.php(557): MediaWiki->doPostOutputShutdown(string)
#18 /var/www/html/go/wiki/index.php(42): MediaWiki->run()
#19 {main}

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