Molecular conservation of estrogen-response associated with cell cycle regulation, hormonal carcinogenesis and cancer in zebrafish and human cancer cell lines
- Lam, S.H., Lee, S.G., Lin, C.Y., Thomsen, J.S., Fu, P.Y., Murthy, K.R., Li, H., Govindarajan, K.R., Nick, L.C., Bourque, G., Gong, Z., Lufkin, T., Liu, E.T., and Mathavan, S.
- BMC Medical Genomics 4(1): 41 (Journal)
- Registered Authors
- Gong, Zhiyuan, Lam, Siew Hong, Mathavan, S.
- MeSH Terms
- Binding Sites
- Cell Cycle/drug effects*
- Cell Cycle/genetics*
- Cell Line, Tumor
- Cluster Analysis
- Down-Regulation/drug effects
- Gene Expression Profiling
- Gene Regulatory Networks/genetics
- Oligonucleotide Array Sequence Analysis
- Precancerous Conditions/genetics*
- Reproducibility of Results
- Response Elements/genetics
- Reverse Transcriptase Polymerase Chain Reaction
- Sequence Homology, Nucleic Acid
- Signal Transduction/drug effects
- Signal Transduction/genetics
- Up-Regulation/drug effects
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- 21575170 Full text @ BMC Med. Genomics
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 (17beta-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-related cancer research.