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) : Farago, Marganit D


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a458412.pdf


Report Date : Jul 2006


Pagination or Media Count : 22


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.


Descriptors :   *NEOPLASMS , *GENES , EPITHELIUM , HIGH RATE , IN VITRO ANALYSIS , CARCINOGENS , MORTALITY RATE , CANCER , PHOSPHORYLATION , TRANSCRIPTION(GENETICS) , BREAST CANCER , MAMMARY GLANDS , NUCLEI , IN VIVO ANALYSIS , MICE , DOSAGE , DEGRADATION , HUMANS


Subject Categories : Genetic Engineering and Molecular Biology
      Anatomy and Physiology
      Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE