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research article

Increased Wnt signaling triggers oncogenic conversion of human breast epithelial cells by a Notch-dependent mechanism

Ayyanan, A.
•
Civenni, G.
•
Ciarloni, L.
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2006
Proceedings Of The National Academy Of Sciences Of The United States Of America (PNAS)

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.

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Type
research article
DOI
10.1073/pnas.0600065103
Web of Science ID

WOS:000236225300054

Author(s)
Ayyanan, A.
•
Civenni, G.
•
Ciarloni, L.
•
Morel, C.
•
Mueller, N.
•
Lefort, K.
•
Mandinova, A.
•
Raffoul, W.
•
Fiche, M.
•
Dotto, G. P.
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Date Issued

2006

Publisher

National Academy of Sciences

Published in
Proceedings Of The National Academy Of Sciences Of The United States Of America (PNAS)
Volume

103

Issue

10

Start page

3799

End page

804

Note

Swiss Institute for Experimental Cancer Research, National Center of Competence in Research in Molecular Oncology, 155 Chemin des Boveresses, CH-1066 Epalinges/Lausanne, Switzerland.

Peer reviewed

REVIEWED

Written at

OTHER

EPFL units
UPBRI  
Available on Infoscience
January 24, 2008
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/17145
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