Effect of glycogen synthase kinase-3 inactivation on mouse mammary gland development and oncogenesis

Many components of Wnt/{beta}-catenin signaling pathway have critical functions in mammary gland development and tumor formation, yet the contribution of glycogen synthase kinase-3 (GSK-3 and GSK-3{beta}) 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 knock-outs 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.