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

• DOI: 10.1073/pnas.0600065103
• Publication Date: 2006-02-25T01:34:46Z
• Authors: Ayyakannu Ayyanan; Gianluca Civenni; Laura Ciarloni; Catherine Morel; Nathalie Mueller; Karine Lefort; Anna Mandinova; Wassim Raffoul; Maryse Fiche; Gian Paolo Dotto; Cathrin Brisken
• Keywords: Ectopic expression; WNT3A; Beta-catenin

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