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

Recent studies have implicated ectopic activation of the Wnt pathway in many human cancers, including breast cancer. B-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 3B (GSK3B) phosphorylation of the NH2-terminal domain of B-catenin targets it for ubiquitination and proteosomal degradation. We hypothesized that expression of kinase-inactive GSK3B (KI-GSK3B) in mammary glands would function in a dominant-negative fashion by antagonizing the endogenous activity of GSK3B and promoting breast cancer development. Consistent with this, we find that KI-GSK3B stabilizes B-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-GSK3B under the control of the mouse mammary tumor virus-long terminal repeat develop mammary tumors with overexpression of B-catenin and cyclin D1. Thus, antagonism of GSK3B activity is oncogenic in the mammary epithelium; mutation or pharmacologic down-regulation of GSK3B could promote mammary tumors. (Cancer Res 2005; 65(13): 5792-801)