Molecular conservation of estrogen-response associated with cell cycle regulation, hormonal carcinogenesis and cancer in zebrafish and human cancer cell lines

• Published in: BMC genomics 2011-05, Vol.4 (1), p.41-41, Article 41
• Main Authors: Lam, Siew Hong, Lee, Serene G P, Lin, Chin Y, Thomsen, Jane S, Fu, Pan Y, Murthy, Karuturi R K, Li, Haixia, Govindarajan, Kunde R, Nick, Lin C H, Bourque, Guillaume, Gong, Zhiyuan, Lufkin, Thomas, Liu, Edison T, Mathavan, Sinnakaruppan
• Format: Article
• Language: English
• Subjects: Animals; anti-estrogen ICI 182,780; Binding Sites; Cancer; carcinogenesis; Cell cycle; Cell Cycle - drug effects; Cell Cycle - genetics; Cell Line, Tumor; Cluster Analysis; Danio rerio; Down-Regulation - drug effects; Estradiol - pharmacology; Estrogen; estrogen-responsive genes; Estrogens - pharmacology; Freshwater; Gene Expression Profiling; Gene Regulatory Networks - genetics; Genes; Genetic aspects; human cancer cell lines; Humans; Male; microarray; model organism; molecular conservation; Neoplasms - genetics; Oligonucleotide Array Sequence Analysis; Physiological aspects; Precancerous Conditions - genetics; Reproducibility of Results; Response Elements - genetics; Reverse Transcriptase Polymerase Chain Reaction; Risk factors; Sequence Homology, Nucleic Acid; Signal Transduction - drug effects; Signal Transduction - genetics; signaling pathways; Up-Regulation - drug effects; zebrafish; Zebrafish - genetics; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 1755-8794; 1471-2164; 1755-8794; 1471-2164
• DOI: 10.1186/1755-8794-4-41

The zebrafish is recognized as a versatile cancer and drug screening model. However, it is not known whether the estrogen-responsive genes and signaling pathways that are involved in estrogen-dependent carcinogenesis and human cancer are operating in zebrafish. In order to determine the potential of zebrafish model for estrogen-related cancer research, we investigated the molecular conservation of estrogen responses operating in both zebrafish and human cancer cell lines. Microarray experiment was performed on zebrafish exposed to estrogen (17β-estradiol; a classified carcinogen) and an anti-estrogen (ICI 182,780). Zebrafish estrogen-responsive genes sensitive to both estrogen and anti-estrogen were identified and validated using real-time PCR. Human homolog mapping and knowledge-based data mining were performed on zebrafish estrogen responsive genes followed by estrogen receptor binding site analysis and comparative transcriptome analysis with estrogen-responsive human cancer cell lines (MCF7, T47D and Ishikawa). Our transcriptome analysis captured multiple estrogen-responsive genes and signaling pathways that increased cell proliferation, promoted DNA damage and genome instability, and decreased tumor suppressing effects, suggesting a common mechanism for estrogen-induced carcinogenesis. Comparative analysis revealed a core set of conserved estrogen-responsive genes that demonstrate enrichment of estrogen receptor binding sites and cell cycle signaling pathways. Knowledge-based and network analysis led us to propose that the mechanism involving estrogen-activated estrogen receptor mediated down-regulation of human homolog HES1 followed by up-regulation cell cycle-related genes (human homologs E2F4, CDK2, CCNA, CCNB, CCNE), is highly conserved, and this mechanism may involve novel crosstalk with basal AHR. We also identified mitotic roles of polo-like kinase as a conserved signaling pathway with multiple entry points for estrogen regulation. The findings demonstrate the use of zebrafish for characterizing estrogen-like environmental carcinogens and anti-estrogen drug screening. From an evolutionary perspective, our findings suggest that estrogen regulation of cell cycle is perhaps one of the earliest forms of steroidal-receptor controlled cellular processes. Our study provides first evidence of molecular conservation of estrogen-responsiveness between zebrafish and human cancer cell lines, hence demonstrating the potential of zebrafish for estrogen-relate