The Role of DN-GSK3b in Mammary Tumorigenesis
Annual summary rept. 1 Jul 2004-30 Jun 2007
BOSTON MEDICAL CENTER CORP MA
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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.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research