title: Increased Wnt signaling triggers oncogenic conversion of human breast epithelial cells by a Notch-dependent mechanism.
abstract: 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.
authors.affiliation: Swiss Institute for Experimental Cancer Research, National Center of Competence in Research in Molecular Oncology, 155 Chemin des Boveresses, CH-1066 Epalinges/Lausanne, Switzerland.
authors.forename: Ayyakannu
authors.initials: A
authors.lastname: Ayyanan
authors.forename: Gianluca
authors.initials: G
authors.lastname: Civenni
authors.forename: Laura
authors.initials: L
authors.lastname: Ciarloni
authors.forename: Catherine
authors.initials: C
authors.lastname: Morel
authors.forename: Nathalie
authors.initials: N
authors.lastname: Mueller
authors.forename: Karine
authors.initials: K
authors.lastname: Lefort
authors.forename: Anna
authors.initials: A
authors.lastname: Mandinova
authors.forename: Wassim
authors.initials: W
authors.lastname: Raffoul
authors.forename: Maryse
authors.initials: M
authors.lastname: Fiche
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Dotto
authors.forename: Cathrin
authors.initials: C
authors.lastname: Brisken
mesh_terms: D000818:Animals; D001940:Breast / Q000166:cytology / Q000378:metabolism*; D001943:Breast Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004249:DNA Damage; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D012334:RNA, Neoplasm; D051880:Receptors, Notch; D051155:Wnt1 Protein