First Author | Dembowy J | Year | 2015 |
Journal | Oncogene | Volume | 34 |
Issue | 27 | Pages | 3514-26 |
PubMed ID | 25195860 | Mgi Jnum | J:222524 |
Mgi Id | MGI:5644781 | Doi | 10.1038/onc.2014.279 |
Citation | Dembowy J, et al. (2015) Effect of glycogen synthase kinase-3 inactivation on mouse mammary gland development and oncogenesis. Oncogene 34(27):3514-26 |
abstractText | Many components of the Wnt/beta-catenin signaling pathway have critical functions in mammary gland development and tumor formation, yet the contribution of glycogen synthase kinase-3 (GSK-3alpha and GSK-3beta) 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/beta-catenin signaling and induces mammary intraepithelial neoplasia that progresses to squamous transdifferentiation and development of adenosquamous carcinomas at 6 months. To uncover possible beta-catenin-independent activities of GSK-3, we generated mammary-specific knockouts of GSK-3 and beta-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 beta-catenin alone. At 10 months, adenocarcinomas that developed in glands lacking GSK-3 and beta-catenin displayed elevated levels of gamma-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. |