title: Effect of glycogen synthase kinase-3 inactivation on mouse mammary gland development and oncogenesis.
abstract: Many components of the Wnt/β-catenin signaling pathway have critical functions in mammary gland development and tumor formation, yet the contribution of glycogen synthase kinase-3 (GSK-3α and GSK-3β) to mammopoiesis and oncogenesis is unclear. Here, we report that WAP-Cre-mediated deletion of GSK-3 in the mammary epithelium results in activation of Wnt/β-catenin signaling and induces mammary intraepithelial neoplasia that progresses to squamous transdifferentiation and development of adenosquamous carcinomas at 6 months. To uncover possible β-catenin-independent activities of GSK-3, we generated mammary-specific knockouts of GSK-3 and β-catenin. Squamous transdifferentiation of the mammary epithelium was largely attenuated, however, mammary epithelial cells lost the ability to form mammospheres suggesting perturbation of stem cell properties unrelated to loss of β-catenin alone. At 10 months, adenocarcinomas that developed in glands lacking GSK-3 and β-catenin displayed elevated levels of γ-catenin/plakoglobin as well as activation of the Hedgehog and Notch pathways. Collectively, these results establish the two isoforms of GSK-3 as essential integrators of multiple developmental signals that act to maintain normal mammary gland function and suppress tumorigenesis.
authors.affiliation: 1] Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Dembowy
authors.affiliation: 1] Pathology Core, Centre for Modelling Human Disease, Toronto Centre for Phenogenomics, Toronto, Ontario, Canada [2] Toronto General Hospital Research Institute, Toronto, Ontario, Canada.
authors.forename: H A
authors.initials: HA
authors.lastname: Adissu
authors.affiliation: Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: J C
authors.initials: JC
authors.lastname: Liu
authors.affiliation: 1] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada [2] Toronto General Hospital Research Institute, Toronto, Ontario, Canada [3] Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Zacksenhaus
authors.affiliation: 1] Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: J R
authors.initials: JR
authors.lastname: Woodgett
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D005260:Female; D020868:Gene Silencing; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics*; D007527:Isoenzymes / Q000235:genetics; D008321:Mammary Glands, Animal / Q000254:growth & development* / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014407:Tumor Cells, Cultured
chemical_list: D007527:Isoenzymes; D038362:Glycogen Synthase Kinase 3