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

Abstract

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

Citation Formats

Pogribny, Igor P., Bagnyukova, Tetyana V., Tryndyak, Volodymyr P., Muskhelishvili, Levan, Rodriguez-Juarez, Rocio, Kovalchuk, Olga, Han Tao, Fuscoe, James C., Ross, Sharon A., and Beland, Frederick A.. Gene expression profiling reveals underlying molecular mechanisms of the early stages of tamoxifen-induced rat hepatocarcinogenesis. United States: N. p., 2007. Web. doi:10.1016/j.taap.2007.07.001.
Pogribny, Igor P., Bagnyukova, Tetyana V., Tryndyak, Volodymyr P., Muskhelishvili, Levan, Rodriguez-Juarez, Rocio, Kovalchuk, Olga, Han Tao, Fuscoe, James C., Ross, Sharon A., & Beland, Frederick A.. Gene expression profiling reveals underlying molecular mechanisms of the early stages of tamoxifen-induced rat hepatocarcinogenesis. United States. doi:10.1016/j.taap.2007.07.001.
Pogribny, Igor P., Bagnyukova, Tetyana V., Tryndyak, Volodymyr P., Muskhelishvili, Levan, Rodriguez-Juarez, Rocio, Kovalchuk, Olga, Han Tao, Fuscoe, James C., Ross, Sharon A., and Beland, Frederick A.. 2007. "Gene expression profiling reveals underlying molecular mechanisms of the early stages of tamoxifen-induced rat hepatocarcinogenesis". United States. doi:10.1016/j.taap.2007.07.001.
@article{osti_21077853,
title = {Gene expression profiling reveals underlying molecular mechanisms of the early stages of tamoxifen-induced rat hepatocarcinogenesis},
author = {Pogribny, Igor P. and Bagnyukova, Tetyana V. and Tryndyak, Volodymyr P. and Muskhelishvili, Levan and Rodriguez-Juarez, Rocio and Kovalchuk, Olga and Han Tao and Fuscoe, James C. and Ross, Sharon A. and Beland, Frederick A.},
abstractNote = {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 of 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.},
doi = {10.1016/j.taap.2007.07.001},
journal = {Toxicology and Applied Pharmacology},
number = 1,
volume = 225,
place = {United States},
year = 2007,
month =
}
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  • No abstract prepared.
  • Bisphenol-A (BPA) shows proliferative actions in uterus and mammary glands and may influence the development of male and female reproductive tracts in utero or during early postnatal life. Because of its ability to function as an estrogen receptor (ER) agonist, BPA has the potential to disrupt normal endocrine signaling through regulation of ER target genes. Some genes are regulated by both estradiol (E2) and BPA, but those exclusive to either agent have not been described. Using a yeast strain incorporating a vitellogenin A2 ERE-LacZ reporter gene into the genome, we found that BPA induced expression of the reporter in coloniesmore » transformed with the ER{alpha} expression plasmid, illustrating BPA-mediated regulation within a chromatin context. Additionally, a reporter gene transiently transfected into the endometrial cancer (Ishikawa) cell line also showed BPA activity, although at 100-fold less potency than E2. To compare global gene expression in response to BPA and E2, we used a variant of the MCF-7 breast cancer cell line stably expressing HA-tagged ER{alpha}. Cultures were treated for 3 h with an ethanol vehicle, E2 (10{sup -8} M), or BPA (10{sup -6} M), followed by isolation of RNA and microarray analysis with the human U95A probe array (Affymetrix, Santa Clara, CA, USA). More than 300 genes were changed 2-fold or more by either or both agents, with roughly half being up-regulated and half down-regulated. A number of growth- and development-related genes, such as HOXC1 and C6, Wnt5A, Frizzled, TGF{beta}-2, and STAT inhibitor 2, were found to be affected exclusively by BPA. We used quantitative real-time PCR to verify regulation of the HOXC6 gene, which showed decreased expression of approximately 2.5-fold by BPA. These results reveal novel effects by BPA and E2, raising interesting possibilities regarding the role of endocrine disruptors in sexual development.« less