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Identification of novel truncated androgen receptor (AR) mutants including unreported pre-mRNA splicing variants in the 22Rv1 hormone-refractory prostate cancer (PCa) cell line

Authors

  • Gemma Marcias,

    1. Signalisation et Cancer de la Prostate, Physiopathologie et Médecine Translationnelle, Université de Strasbourg, Strasbourg, France
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  • Eva Erdmann,

    1. Signalisation et Cancer de la Prostate, Physiopathologie et Médecine Translationnelle, Université de Strasbourg, Strasbourg, France
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  • Gaëlle Lapouge,

    1. Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles, Brussels, Belgium
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  • Christelle Siebert,

    1. Signalisation et Cancer de la Prostate, Physiopathologie et Médecine Translationnelle, Université de Strasbourg, Strasbourg, France
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  • Philippe Barthélémy,

    1. Signalisation et Cancer de la Prostate, Physiopathologie et Médecine Translationnelle, Université de Strasbourg, Strasbourg, France
    2. Service d'Hématologie et d'Oncologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
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  • Brigitte Duclos,

    1. Service d'Hématologie et d'Oncologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
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  • Jean-Pierre Bergerat,

    1. Signalisation et Cancer de la Prostate, Physiopathologie et Médecine Translationnelle, Université de Strasbourg, Strasbourg, France
    2. Service d'Hématologie et d'Oncologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
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  • Jocelyn Céraline,

    Corresponding author
    1. Signalisation et Cancer de la Prostate, Physiopathologie et Médecine Translationnelle, Université de Strasbourg, Strasbourg, France
    2. Service d'Hématologie et d'Oncologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
    • Université de Strasbourg, Faculté de Médecine, EA4438, Physiopathologie et Médecine translationnelle, Signalisation et Cancer de la Prostate, 1 place de l'Hôpital, 67000 Strasbourg, France
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  • Jean-Emmanuel Kurtz

    1. Signalisation et Cancer de la Prostate, Physiopathologie et Médecine Translationnelle, Université de Strasbourg, Strasbourg, France
    2. Service d'Hématologie et d'Oncologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
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  • Communicated by Bruce Gottlieb

Abstract

Advanced prostate cancer (PCa) has emerged as a public health concern due to population aging. Although androgen deprivation has proven efficacy in this condition, most advanced PCa patients will have to face failure of androgen deprivation as a treatment. Mutations in the androgen receptor (AR) from tumor cells have been shown to induce androgen independency both in PCa cell lines and in the clinic. We have investigated the molecular events leading to androgen independency in the 22Rv1 cell line, a commonly used preclinical model of PCa. Besides AR mutants that have been described so far, including nonsense mutations, recent data have focused on AR pre-mRNA aberrant splicing as a new mechanism leading to constitutively active truncated AR variants. In this article, we describe two novel variants arising from aberrant splicing of AR pre-mRNA, characterized by long mRNA transcripts that encode truncated, constitutively active proteins. We also describe several new nonsense mutants that share ligand independency and transcriptional activity. Finally, we show that alongside these mutants, 22Rv1 cells also express a mutant AR lacking exon 3 tandem duplication, a major feature of this cell line. By describing unreported AR mutants in the 22Rv1 cell line, our data emphasize the complexity and heterogeneity of molecular events that occur in preclinical models, and supposedly in the clinic. Future work on the 22Rv1 cell line should take into account the concomitant expression of various AR mutants. Hum Mutat 31:74–80, 2010. © 2009 Wiley-Liss, Inc.

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