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Identification of transcription factors associated with castration-resistance: Is the serum responsive factor a potential therapeutic target?

Authors

  • Maria Prencipe,

    Corresponding author
    1. UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland
    • UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, D4, Dublin, Ireland.
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  • Stephen F. Madden,

    1. National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland
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  • Amanda O'Neill,

    1. UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland
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  • Gillian O'Hurley,

    1. OncoMark Limited, NovaUCD, Belfield Innovation Park, Belfield, Dublin, Ireland
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  • Aedin Culhane,

    1. Department of Biostatistics, Dana-Farber Cancer Institute, Boston, Massachusetts
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  • Darran O'Connor,

    1. UCD School of Biomolecular and Biomedical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland
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  • Helmut Klocker,

    1. Department of Urology, Innsbruck Medical University, Anichstraße, Innsbruck, Austria
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  • Elaine W. Kay,

    1. Department of Pathology, RCSI Education and Research Center, Beaumont Hospital, Dublin, Ireland
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  • William M. Gallagher,

    1. OncoMark Limited, NovaUCD, Belfield Innovation Park, Belfield, Dublin, Ireland
    2. UCD School of Biomolecular and Biomedical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland
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  • William R. Watson

    1. UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland
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Abstract

BACKGROUND

Advanced prostate cancer is treated by hormone ablation therapy. However, despite an initial response, the majority of men relapse to develop castration-resistant disease for which there are no effective treatments.

We have previously shown that manipulating individual proteins has only minor alterations on the resistant phenotype so we hypothesize that targeting the central transcription factors (TFs) would represent a better therapeutic approach.

METHODS

We have undertaken a transcriptomic analysis of gene expression differences between the androgen-dependent LNCaP parental cells and its castration-resistant Abl and Hof sublines, revealing 1,660 genes associated with castration-resistance. Using effective bioinformatic techniques, these transcriptomic data were integrated with TF binding sites resulting in a list of TFs associated with the differential gene expression observed.

RESULTS

Following validation of the gene-chip results, the serum response factor (SRF) was chosen for clinical validation and functional analysis due to its recent association with prostate cancer progression. SRF immunoreactivity in prostate tumor samples was shown for the first time to be associated with castration-resistance. SRF inhibition by siRNA and the small molecule inhibitor CCG-1423 resulted in decreased proliferation.

CONCLUSION

SRF is a key TF by which resistant cells survive with depleted levels of androgens representing a target for therapeutic manipulation. Prostate 73: 743–753, 2013. © 2013 Wiley Periodicals, Inc.

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