Kinase-Inactive Glycogen Synthase Kinase 3β Promotes Wnt Signaling and Mammary Tumorigenesis

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Abstract
Recent studies have implicated ectopic activation of the Wnt pathway in many human cancers, including breast cancer. β-catenin is a critical coactivator in this signaling pathway and is regulated in a complex fashion by phosphorylation, degradation, and nuclear translocation. Glycogen synthase kinase 3β (GSK3β) phosphorylation of the NH2-terminal domain of β-catenin targets it for ubiquitination and proteosomal degradation. We hypothesized that expression of kinase-inactive GSK3β (KI-GSK3β) in mammary glands would function in a dominant-negative fashion by antagonizing the endogenous activity of GSK3β and promoting breast cancer development. Consistent with this, we find that KI-GSK3β stabilizes β-catenin expression, catalyzes its localization to the nucleus, and up-regulates the downstream target gene, cyclin D1, in vitro. In vivo, transgenic mice overexpressing the KI-GSK3β under the control of the mouse mammary tumor virus-long terminal repeat develop mammary tumors with overexpression of β-catenin and cyclin D1. Thus, antagonism of GSK3β activity is oncogenic in the mammary epithelium; mutation or pharmacologic down-regulation of GSK3β could promote mammary tumors.