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Increased Wnt Signaling Triggers Oncogenic Conversion of Human Breast Epithelial Cells by a Notch-Dependent Mechanism
Ayyakannu Ayyanan, Gianluca Civenni, Laura Ciarloni, Catherine Morel, Nathalie Mueller, Karine Lefort, Anna Mandinova, Wassim Raffoul, Maryse Fiche, Gian Paolo Dotto and Cathrin Brisken
Proceedings of the National Academy of Sciences of the United States of America
Vol. 103, No. 10 (Mar. 7, 2006), pp. 3799-3804
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/30048667
Page Count: 6
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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-l-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 Dll, 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.
Proceedings of the National Academy of Sciences of the United States of America © 2006 National Academy of Sciences