The Role of DN-GSK3Beta 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 over-expression of Beta-catenin and cyclin D1. Thus, antagonism of GSK3beta activity is oncogenic in the mammary epithelium; mutation or pharmacologic downregulation of GSK3beta could promote mammary tumors.

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Document Details

Document Type
Technical Report
Publication Date
Jul 01, 2005
Accession Number
ADA439259

Entities

People

  • Marganit D. Farago

Organizations

  • Boston Medical Center

Tags

DTIC Thesaurus Topics

  • Blood
  • Breast Cancer
  • Cancer
  • Carcinoma
  • Cell Line
  • Cell Physiological Processes
  • Cells
  • Chemistry
  • Environmental Health
  • Epithelium
  • Gene Expression
  • Genetically Modified Organisms
  • Mammary Glands
  • Metabolism
  • Neoplasms
  • Oncology
  • Tissues

Fields of Study

  • Biology

Readers

  • Cellular and Molecular Pathways of Apoptosis.
  • Molecular Biology and Genetics