title: Modeling ductal carcinoma in situ: a HER2-Notch3 collaboration enables luminal filling.
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.
authors: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.
authors: C-R
authors: CR
authors: Pradeep
authors: W J
authors: WJ
authors: Köstler
authors: M
authors: M
authors: Lauriola
authors: R Z
authors: RZ
authors: Granit
authors: F
authors: F
authors: Zhang
authors: J
authors: J
authors: Jacob-Hirsch
authors: G
authors: G
authors: Rechavi
authors: H B
authors: HB
authors: Nair
authors: B T
authors: BT
authors: Hennessy
authors: A M
authors: AM
authors: Gonzalez-Angulo
authors: R R
authors: RR
authors: Tekmal
authors: I
authors: I
authors: Ben-Porath
authors: G B
authors: GB
authors: Mills
authors: E
authors: E
authors: Domany
authors: Y
authors: Y
authors: Yarden
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D042361:Mammary Glands, Human / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D014162:Transfection
chemical_list: D004815:Epidermal Growth Factor; D049452:Green Fluorescent Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D000071656:Receptor, Notch3; D051880:Receptors, Notch; C499374:NOTCH3 protein, human