PT  - JOURNAL ARTICLE
AU  - Joanna Dembowy
AU  - Hibret A. Adissu
AU  - Jeff C. Liu
AU  - Eldad Zacksenhaus
AU  - James R. Woodgett
TI  - Effect of glycogen synthase kinase-3 inactivation on mouse mammary gland development and oncogenesis
AID  - 10.1101/001321
DP  - 2013 Jan 01
TA  - bioRxiv
PG  - 001321
4099  - http://biorxiv.org/content/early/2013/12/10/001321.short
4100  - http://biorxiv.org/content/early/2013/12/10/001321.full
AB  - Many components of 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 knock-outs 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.