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.
Highlights
Epithelial malignancies, including those of the breast, are thought to initiate in stem-like cells defined by their capacity to self-renew and persist long enough to sustain and propagate mutations, as well as generate all functional cell types within a given tissue
To investigate the functions of glycogen synthase kinase (GSK)-3s in the mammary gland, we generated GSK-3α− / −; GSK-3βExon[2] LoxP/Exon[2] LoxP, referred to as GSK-3α− / −; GSK-3βFL/FL mice with mammary-gland-selective deletion of the floxed GSK-3β alleles achieved by Cre-mediated recombination driven by the whey acidic protein (WAP) promoter yielding WAP-GSK-3 double knockout animals (WAP-DKO)
Expression of the WAP-Cre transgene can be detected during the estrus stage of the murine estrus cycle and the WAP promoter is substantially increased during each pregnancy when WAP expression is observed in both ductal and alveolar epithelial cells, starting from 15 days post coitum.[58,59,60]
Summary
Epithelial malignancies, including those of the breast, are thought to initiate in stem-like cells defined by their capacity to self-renew and persist long enough to sustain and propagate mutations, as well as generate all functional cell types within a given tissue. These ‘tumor-initiating cells’ (TICs) may arise from normal adult stem cells as a consequence of alterations in the regulation of balance between self-renewal and differentiation or from more committed progenitors that have re-acquired stem cell characteristics during transformation.[1,2] The contribution of distinct stem/progenitor cells to breast cancer heterogeneity remains obscure. Inhibition of GSK-3 is critical to canonical Wnt signaling leading to increased β-catenin levels associated with elevated proliferation and suppression of differentiation in a number of tissues.[4,5,6,7] GSK-3 has been shown to interact with Hh pathway components at several levels to inhibit transcriptional functions of Gli proteins.[8,9,10,11] Several cell line studies have demonstrated that GSK-3 inhibition modulates Notch signaling, at least in part by phosphorylating the Notch intracellular domain (NICD), thereby preventing nuclear entry and efficient association with its target gene promoters.[12,13,14]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
