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

¹ Molecular Medicine Program, Department of Medicine, Boston University Medical Center, Boston, Massachusetts and ² Center for Comparative Medicine, University of California-Davis, Davis, California

Requests for reprints: David C. Seldin, 650 Albany Street, Boston, MA 02118. Phone: 617-638-7027; Fax: 617-638-7530; E-mail: dseldin{at}bumc.bu.edu.

Recent studies have implicated ectopic activation of the Wnt pathway in many human cancers, including breast cancer. ß-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 3ß (GSK3ß) phosphorylation of the NH₂-terminal domain of ß-catenin targets it for ubiquitination and proteosomal degradation. We hypothesized that expression of kinase-inactive GSK3ß (KI-GSK3ß) in mammary glands would function in a dominant-negative fashion by antagonizing the endogenous activity of GSK3ß and promoting breast cancer development. Consistent with this, we find that KI-GSK3ß stabilizes ß-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-GSK3ß under the control of the mouse mammary tumor virus-long terminal repeat develop mammary tumors with overexpression of ß-catenin and cyclin D1. Thus, antagonism of GSK3ß activity is oncogenic in the mammary epithelium; mutation or pharmacologic down-regulation of GSK3ß could promote mammary tumors.

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