Guangzhou Han

Fred Hutchinson Cancer Research Center, Seattle, Washington, United States

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Publications (2)14.82 Total impact

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    ABSTRACT: Mutations in the androgen receptor (AR) have been detected in experimental and clinical prostate tumors. Mice with enforced prostate-specific expression of one such receptor variant, AR-E231G, invariably develop prostatic intraepithelial neoplasia by 12 weeks and metastatic prostate cancer by 52 weeks. The aim of this study was to identify genes with altered expression in the prostates of AR-E231G mice at an early stage of disease that may act as drivers of AR-mediated tumorigenesis. The gene expression profile of AR-E231G prostate tissue from 12-week-old mice was compared to an equivalent profile from mice expressing the AR-T857A receptor variant (analogous to the AR-T877A variant in LNCaP cells), which do not develop prostate tumors. One hundred and thirty-two genes were differentially expressed in AR-E231G prostates. Classification of these genes revealed enrichment for cellular pathways known to be involved in prostate cancer, including cell cycle and lipid metabolism. Suppression of two genes upregulated in the AR-E231G model, ADM and CITED1, increased cell death and reduced proliferation of human prostate cancer cells. Many genes differentially expressed in AR-E231G prostates are also deregulated in human tumors. Three of these genes, ID4, NR2F1 and PTGDS, which were expressed at consistently lower levels in clinical prostate cancer compared to nonmalignant tissues, formed a signature that predicted biochemical relapse (hazard ratio 2.2, p = 0.038). We believe that our findings support the value of this novel mouse model of prostate cancer to identify candidate therapeutic targets and/or biomarkers of human disease.
    International Journal of Cancer 08/2012; 131(3):662-72. DOI:10.1002/ijc.26414 · 5.01 Impact Factor
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    ABSTRACT: Recent evidence demonstrates that the androgen receptor (AR) continues to influence prostate cancer growth despite medical therapies that reduce circulating androgen ligands to castrate levels and/or block ligand binding. Whereas the mutation, amplification, overexpression of AR, or cross-talk between AR and other growth factor pathways may explain the failure of androgen ablation therapies in some cases, there is little evidence supporting a causal role between AR and prostate cancer. In this study, we functionally and directly address the role whereby AR contributes to spontaneous cancer progression by generating transgenic mice expressing (i) AR-WT to recapitulate increased AR levels and ligand sensitivity, (ii) AR-T857A to represent a promiscuous AR ligand response, and (iii) AR-E231G to model altered AR function. Whereas transgenes encoding either AR-WT or AR-T857A did not cause prostate cancer when expressed at equivalent levels, expression of AR-E231G, which carries a mutation in the most highly conserved signature motif of the NH2-terminal domain that also influences interactions with cellular coregulators, caused rapid development of prostatic intraepithelial neoplasia that progressed to invasive and metastatic disease in 100% of mice examined. Taken together, our data now demonstrate the oncogenic potential of steroid receptors and implicate altered AR function and receptor coregulator interaction as critical determinants of prostate cancer initiation, invasion, and metastasis.
    Proceedings of the National Academy of Sciences 02/2005; 102(4):1151-6. DOI:10.1073/pnas.0408925102 · 9.81 Impact Factor

Publication Stats

153 Citations
14.82 Total Impact Points

Institutions

  • 2012
    • Fred Hutchinson Cancer Research Center
      • Division of Clinical Research
      Seattle, Washington, United States
  • 2005
    • Centre for Cellular and Molecular Biology
      Bhaganagar, Andhra Pradesh, India