Kinase-inactive glycogen synthase kinase 3β promotes Wnt signaling and mammary tumorigenesis

Recent studies have implicated ectopic activation of the Wnt pathway in many human cancers, including breast cancer. beta-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 3 beta (GSK3 beta) phosphorylation of the NH2-terminal domain of beta-catenin targets it for ubiquitination and proteosomal degradation. We hypothesized that expression of kinase-inactive GSK3 beta (KI-GSK3 beta) in mammary glands would function in a dominant-negative fashion by antagonizing the endogenous activity of GSK3 beta and promoting breast cancer development. Consistent with this, we rind that KI-GSK3 beta stabilizes beta-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-GSK3 beta under the control of the mouse mammary tumor virus-long terminal repeat develop mammary tumors with overexpression of beta-catenin and cyclin D1. Thus, antagonism of GSK3 beta activity is oncogenic in the mammary epithelium; mutation or pharmacologic down-regulation of GSK3 beta could promote mammary tumors.