title: Molecular conservation of estrogen-response associated with cell cycle regulation, hormonal carcinogenesis and cancer in zebrafish and human cancer cell lines.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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-related cancer research.
authors.affiliation: Genome Institute of Singapore, #02-01Genome, 60 Biopolis Street, 138672 Singapore.
authors.forename: Siew Hong
authors.initials: SH
authors.lastname: Lam
authors.forename: Serene G P
authors.initials: SG
authors.lastname: Lee
authors.forename: Chin Y
authors.initials: CY
authors.lastname: Lin
authors.forename: Jane S
authors.initials: JS
authors.lastname: Thomsen
authors.forename: Pan Y
authors.initials: PY
authors.lastname: Fu
authors.forename: Karuturi R K
authors.initials: KR
authors.lastname: Murthy
authors.forename: Haixia
authors.initials: H
authors.lastname: Li
authors.forename: Kunde R
authors.initials: KR
authors.lastname: Govindarajan
authors.forename: Lin C H
authors.initials: LC
authors.lastname: Nick
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bourque
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Gong
authors.forename: Thomas
authors.initials: T
authors.lastname: Lufkin
authors.forename: Edison T
authors.initials: ET
authors.lastname: Liu
authors.forename: Sinnakaruppan
authors.initials: S
authors.lastname: Mathavan
mesh_terms: D000818:Animals; D001665:Binding Sites; D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics*; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D015536:Down-Regulation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks / Q000235:genetics; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011230:Precancerous Conditions / Q000235:genetics*; D015203:Reproducibility of Results; D020218:Response Elements / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D015027:Zebrafish / Q000235:genetics*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D004967:Estrogens; D029961:Zebrafish Proteins; D004958:Estradiol