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 of tamoxifen-induced hepatocarcinogenesis is dysregulation of signaling pathways in cell cycle progression from the G(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.
authors: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA. igor.pogribny@fda.hhs.gov
authors: Igor P
authors: IP
authors: Pogribny
authors: Tetyana V
authors: TV
authors: Bagnyukova
authors: Volodymyr P
authors: VP
authors: Tryndyak
authors: Levan
authors: L
authors: Muskhelishvili
authors: Rocio
authors: R
authors: Rodriguez-Juarez
authors: Olga
authors: O
authors: Kovalchuk
authors: Tao
authors: T
authors: Han
authors: James C
authors: JC
authors: Fuscoe
authors: Sharon A
authors: SA
authors: Ross
authors: Frederick A
authors: FA
authors: Beland
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004965:Estrogen Antagonists / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology*; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D011916:Rats, Inbred F344; D016196:S Phase / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000378:metabolism / Q000633:toxicity*; D013997:Time Factors
chemical_list: D002273:Carcinogens; D004965:Estrogen Antagonists; D013629:Tamoxifen