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Open Access Research article

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

Siew Hong Lam24, Serene GP Lee1, Chin Y Lin135, Jane S Thomsen1, Pan Y Fu1, Karuturi RK Murthy1, Haixia Li1, Kunde R Govindarajan1, Lin CH Nick1, Guillaume Bourque1, Zhiyuan Gong2, Thomas Lufkin1, Edison T Liu1* and Sinnakaruppan Mathavan1*

Author Affiliations

1 Genome Institute of Singapore, #02-01Genome, 60 Biopolis Street, 138672, Singapore

2 Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, 117543, Singapore

3 Department of Microbiology and Molecular Biology, Brigham Young University, 753 WIDB, Provo, UT 84602, USA

4 NUS Environmental Research Institute (NERI), TL #02-02, Engineering Drive 1, 117411, Singapore

5 Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, 3013 Science & Engineering Research Center, Houston, TX 77204, USA

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BMC Medical Genomics 2011, 4:41  doi:10.1186/1755-8794-4-41

Published: 16 May 2011

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.

Conclusion

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.

Keywords:
zebrafish; microarray; estrogen; anti-estrogen ICI 182,780; estrogen-responsive genes; signaling pathways; carcinogenesis; human cancer cell lines; molecular conservation; model organism