Modeling ductal carcinoma in situ: a HER2-Notch3 collaboration enables luminal filling.

Hdl Handle:
http://hdl.handle.net/10147/230452
Title:
Modeling ductal carcinoma in situ: a HER2-Notch3 collaboration enables luminal filling.
Authors:
Pradeep, C-R; Köstler, W J; Lauriola, M; Granit, R Z; Zhang, F; Jacob-Hirsch, J; Rechavi, G; Nair, H B; Hennessy, B T; Gonzalez-Angulo, A M; Tekmal, R R; Ben-Porath, I; Mills, G B; Domany, E; Yarden, Y
Affiliation:
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.
Citation:
Modeling ductal carcinoma in situ: a HER2-Notch3 collaboration enables luminal filling. 2012, 31 (7):907-17 Oncogene
Journal:
Oncogene
Issue Date:
16-Feb-2012
URI:
http://hdl.handle.net/10147/230452
DOI:
10.1038/onc.2011.279
PubMed ID:
21743488
Abstract:
A large fraction of ductal carcinoma in situ (DCIS), a non-invasive precursor lesion of invasive breast cancer, overexpresses the HER2/neu oncogene. The ducts of DCIS are abnormally filled with cells that evade apoptosis, but the underlying mechanisms remain incompletely understood. We overexpressed HER2 in mammary epithelial cells and observed growth factor-independent proliferation. When grown in extracellular matrix as three-dimensional spheroids, control cells developed a hollow lumen, but HER2-overexpressing cells populated the lumen by evading apoptosis. We demonstrate that HER2 overexpression in this cellular model of DCIS drives transcriptional upregulation of multiple components of the Notch survival pathway. Importantly, luminal filling required upregulation of a signaling pathway comprising Notch3, its cleaved intracellular domain and the transcriptional regulator HES1, resulting in elevated levels of c-MYC and cyclin D1. In line with HER2-Notch3 collaboration, drugs intercepting either arm reverted the DCIS-like phenotype. In addition, we report upregulation of Notch3 in hyperplastic lesions of HER2 transgenic animals, as well as an association between HER2 levels and expression levels of components of the Notch pathway in tumor specimens of breast cancer patients. Therefore, it is conceivable that the integration of the Notch and HER2 signaling pathways contributes to the pathophysiology of DCIS.
Item Type:
Article
Language:
en
MeSH:
Animals; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Cell Line; Cell Proliferation; Epidermal Growth Factor; Epithelial Cells; Female; Gene Expression Profiling; Green Fluorescent Proteins; HEK293 Cells; Humans; Immunoblotting; Mammary Glands, Human; Mice; Mice, Transgenic; Microscopy, Confocal; Models, Biological; Oligonucleotide Array Sequence Analysis; RNA Interference; Receptor, erbB-2; Receptors, Notch; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Transfection
ISSN:
1476-5594

Full metadata record

DC FieldValue Language
dc.contributor.authorPradeep, C-Ren_GB
dc.contributor.authorKöstler, W Jen_GB
dc.contributor.authorLauriola, Men_GB
dc.contributor.authorGranit, R Zen_GB
dc.contributor.authorZhang, Fen_GB
dc.contributor.authorJacob-Hirsch, Jen_GB
dc.contributor.authorRechavi, Gen_GB
dc.contributor.authorNair, H Ben_GB
dc.contributor.authorHennessy, B Ten_GB
dc.contributor.authorGonzalez-Angulo, A Men_GB
dc.contributor.authorTekmal, R Ren_GB
dc.contributor.authorBen-Porath, Ien_GB
dc.contributor.authorMills, G Ben_GB
dc.contributor.authorDomany, Een_GB
dc.contributor.authorYarden, Yen_GB
dc.date.accessioned2012-06-25T09:29:11Z-
dc.date.available2012-06-25T09:29:11Z-
dc.date.issued2012-02-16-
dc.identifier.citationModeling ductal carcinoma in situ: a HER2-Notch3 collaboration enables luminal filling. 2012, 31 (7):907-17 Oncogeneen_GB
dc.identifier.issn1476-5594-
dc.identifier.pmid21743488-
dc.identifier.doi10.1038/onc.2011.279-
dc.identifier.urihttp://hdl.handle.net/10147/230452-
dc.description.abstractA large fraction of ductal carcinoma in situ (DCIS), a non-invasive precursor lesion of invasive breast cancer, overexpresses the HER2/neu oncogene. The ducts of DCIS are abnormally filled with cells that evade apoptosis, but the underlying mechanisms remain incompletely understood. We overexpressed HER2 in mammary epithelial cells and observed growth factor-independent proliferation. When grown in extracellular matrix as three-dimensional spheroids, control cells developed a hollow lumen, but HER2-overexpressing cells populated the lumen by evading apoptosis. We demonstrate that HER2 overexpression in this cellular model of DCIS drives transcriptional upregulation of multiple components of the Notch survival pathway. Importantly, luminal filling required upregulation of a signaling pathway comprising Notch3, its cleaved intracellular domain and the transcriptional regulator HES1, resulting in elevated levels of c-MYC and cyclin D1. In line with HER2-Notch3 collaboration, drugs intercepting either arm reverted the DCIS-like phenotype. In addition, we report upregulation of Notch3 in hyperplastic lesions of HER2 transgenic animals, as well as an association between HER2 levels and expression levels of components of the Notch pathway in tumor specimens of breast cancer patients. Therefore, it is conceivable that the integration of the Notch and HER2 signaling pathways contributes to the pathophysiology of DCIS.en_GB
dc.language.isoenen
dc.rightsArchived with thanks to Oncogeneen_GB
dc.subject.meshAnimals-
dc.subject.meshBreast Neoplasms-
dc.subject.meshCarcinoma, Intraductal, Noninfiltrating-
dc.subject.meshCell Line-
dc.subject.meshCell Proliferation-
dc.subject.meshEpidermal Growth Factor-
dc.subject.meshEpithelial Cells-
dc.subject.meshFemale-
dc.subject.meshGene Expression Profiling-
dc.subject.meshGreen Fluorescent Proteins-
dc.subject.meshHEK293 Cells-
dc.subject.meshHumans-
dc.subject.meshImmunoblotting-
dc.subject.meshMammary Glands, Human-
dc.subject.meshMice-
dc.subject.meshMice, Transgenic-
dc.subject.meshMicroscopy, Confocal-
dc.subject.meshModels, Biological-
dc.subject.meshOligonucleotide Array Sequence Analysis-
dc.subject.meshRNA Interference-
dc.subject.meshReceptor, erbB-2-
dc.subject.meshReceptors, Notch-
dc.subject.meshReverse Transcriptase Polymerase Chain Reaction-
dc.subject.meshSignal Transduction-
dc.subject.meshTransfection-
dc.titleModeling ductal carcinoma in situ: a HER2-Notch3 collaboration enables luminal filling.en_GB
dc.typeArticleen
dc.contributor.departmentDepartment of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.en_GB
dc.identifier.journalOncogeneen_GB
dc.description.provinceLeinsteren

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