Accession Number:

ADA458412

Title:

The Role of DN-GSK3beta in Mammary Tumorigenesis

Descriptive Note:

Annual summary 1 Jul 2005-30 Jun 2006

Corporate Author:

BOSTON MEDICAL CENTER CORP MA

Personal Author(s):

Report Date:

2006-07-01

Pagination or Media Count:

22.0

Abstract:

Recent studies have implicated ectopic activation of the Wnt pathway in many human cancers, including breast cancer. b-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-3b GSK3b phosphorylation of the N-terminal domain of bcatenin targets it for ubiquitination and proteosomal degradation. We hypothesized that expression of dominant negative DN 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 DN-GSK3b stabilizes b-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-GSK3b under the control of the MMTV-LTR develop mammary tumors with over-expression of bcatenin and cyclin D1. In addition, low dose of carcinogen treatment DMBA accelerates mammary tumor formation in DNGSK3b mice and exhibits a higher mortality rate than untreated transgenic mice. Thus, antagonism of GSK3b activity is oncogenic in the mammary epithelium mutation or pharmacologic downregulation of GSK3b could promote mammary tumors. Moreover, carcinogen treatment accelerates tumorigenesis in mice that have a genetic predisposition to breast cancer.

Subject Categories:

  • Genetic Engineering and Molecular Biology
  • Anatomy and Physiology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE