The Role of DN-GSK3b in Mammary Tumorigenesis
Abstract
Recent studies have implicated ectopic activation of the Wnt pathway in many human cancers, including breast cancer. beta-catenin is a critical co-activator in this signaling pathway, and is regulated in a complex fashion by phosphorylation, degradation, and nuclear translocation. Glycogen synthase kinase-3beta (GSK3beta) phosphorylation of the N-terminal domain of beta-catenin targets it for ubiquitination and proteosomal degradation. We hypothesized that expression of dominant negative (DN) GSK3beta in mammary glands would function in a dominant negative fashion by antagonizing the endogenous activity of GSK3beta and promoting breast cancer development. Consistent with this, we find that DN-GSK3beta stabilizes beta-catenin expression, catalyzes its localization to the nucleus, and upregulates the downstream target gene, cyclin D1, in vitro. In vivo, transgenic mice overexpressing the DN-GSK3beta under the control of the MMTV-LTR develop mammary tumors with overexpression of beta-catenin and cyclin D1. In addition, low dose of carcinogen treatment (DMBA) accelerates mammary tumor formation in DN-GSK3beta mice and exhibits a higher mortality rate than untreated transgenic mice. Thus, antagonism of GSK3beta activity is oncogenic in the mammary epithelium; mutation or pharmacologic downregulation of GSK3betya could promote mammary tumors. Moreover, carcinogen treatment accelerates tumorigenesis in mice that have a genetic predisposition to breast cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2007
- Accession Number
- ADA472118
Entities
People
- Marganit D. Farago
Organizations
- Boston Medical Center