skip to main content

Title: Gene expression profiling reveals underlying molecular mechanisms of the early stages of tamoxifen-induced rat hepatocarcinogenesis

Tamoxifen is a widely used anti-estrogenic drug for chemotherapy and, more recently, for the chemoprevention of breast cancer. Despite the indisputable benefits of tamoxifen in preventing the occurrence and re-occurrence of breast cancer, the use of tamoxifen has been shown to induce non-alcoholic steatohepatitis, which is a life-threatening fatty liver disease with a risk of progression to cirrhosis and hepatocellular carcinoma. In recent years, the high-throughput microarray technology for large-scale analysis of gene expression has become a powerful tool for increasing the understanding of the molecular mechanisms of carcinogenesis and for identifying new biomarkers with diagnostic and predictive values. In the present study, we used the high-throughput microarray technology to determine the gene expression profiles in the liver during early stages of tamoxifen-induced rat hepatocarcinogenesis. Female Fisher 344 rats were fed a 420 ppm tamoxifen containing diet for 12 or 24 weeks, and gene expression profiles were determined in liver of control and tamoxifen-exposed rats. The results indicate that early stages of tamoxifen-induced liver carcinogenesis are characterized by alterations in several major cellular pathways, specifically those involved in the tamoxifen metabolism, lipid metabolism, cell cycle signaling, and apoptosis/cell proliferation control. One of the most prominent changes during early stages ofmore » tamoxifen-induced hepatocarcinogenesis is dysregulation of signaling pathways in cell cycle progression from the G{sub 1} to S phase, evidenced by the progressive and sustained increase in expression of the Pdgfc, Calb3, Ets1, and Ccnd1 genes accompanied by the elevated level of the PI3K, p-PI3K, Akt1/2, Akt3, and cyclin B, D1, and D3 proteins. The early appearance of these alterations suggests their importance in the mechanism of neoplastic cell transformation induced by tamoxifen.« less
Authors:
 [1] ; ;  [2] ;  [3] ; ;  [4] ; ;  [5] ;  [6] ;  [2]
  1. Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States), E-mail: igor.pogribny@fda.hhs.gov
  2. Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States)
  3. Toxicologic Pathology Associates, National Center for Toxicological Research, Jefferson, AR 72079 (United States)
  4. Department of Biological Sciences, University of Lethbridge, AB, Canada T1K3M4 (United States)
  5. Division of Systems Toxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States)
  6. Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20892 (United States)
Publication Date:
OSTI Identifier:
21077853
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 225; Journal Issue: 1; Other Information: DOI: 10.1016/j.taap.2007.07.001; PII: S0041-008X(07)00299-2; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; BIOLOGICAL MARKERS; CARCINOGENESIS; CELL CYCLE; CELL PROLIFERATION; CELL TRANSFORMATIONS; CHEMOTHERAPY; DIET; DRUGS; GENES; HEPATOMAS; LIPIDS; LIVER; MAMMARY GLANDS; METABOLISM; MICROARRAY TECHNOLOGY; PROTEINS; RATS; TAMOXIFEN