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  • Original Article
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Androgen receptor mutation (T877A) promotes prostate cancer cell growth and cell survival

Oncogene volume 25, pages 3905–3913 (2006)Cite this article

Abstract

Alteration of the AR functions due to amplification, overexpression and somatic mutation of the AR itself or altered interaction of AR with other cell growth regulatory proteins, may contribute to a significant subset of advanced prostate cancer (CaP). Very little is known about the pathways impacted by AR dysfunctions, although CaP associated AR alterations suggest the biological role of the AR dysfunction in disease progression. Comparative evaluations of wild type (wt) AR and mutant (mt) ARs in appropriate experimental models should provide a better understanding of the functional impact of AR alterations in CaP. Here, we provide direct evidence showing cell growth/cell survival promoting effects of the widely studied CaP associated AR mutation (T877A). In contrast to Ad-wtAR or Ad-control infected LNCaP or LAPC4 cells, Ad-mtAR (T877A) infected LNCaP or LAPC4 cells continued to grow in the androgen-deprived medium and exhibited an androgen independent AR-transcription factor activity. Further, Ad-mtAR (T877A) infected LNCaP or LAPC4 cells exhibited enhanced cell growth in the presence of lower concentrations of the synthetic androgen, R1881. Of note, Ad-mtAR (T877A) infected LNCaP cells showed striking resistance to cell growth inhibition/apoptosis mediated by the wt p53. Taken together, these findings provide novel insights into the AR dysfunctions resulting from the T877A mutation and functionally similar AR alterations may provide selective cell growth/survival advantage for CaP progression. These observations have important implications for developing biology-based prognostic biomarkers and therapeutic strategies for CaP showing such AR dysfunctions.

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Abbreviations

AR:

androgen receptor

wt:

wild-type

mt:

mutant

CaP:

prostate cancer

FBS:

fetal bovine serum

cFBS:

charcoal/dextran stripped FBS

pfu:

plaque-forming unit

GAPDH:

glyceraldehyde phosphate dehydrogenase

PSA:

prostate specific antigen

Dx:

doxorubicin

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Acknowledgements

We thank Drs Lionel Bañez, Katsuaki Masuda, Kee-Hong Kim and Ms Jennifer Regalia for the helpful suggestions. This research was supported by a grant from the Center for Prostate Disease Research Program through the Henry M Jackson Foundation for the Advancement of Military Medicine (Rockville, MD), funded by the US Army Medical Research and Materiel Command under contract number HU001-04-C-1502 (2004) with the Uniformed Services University. The opinions and assertions contained herein are the private views of the authors and are not to be considered as reflecting the views of the US Army or the Department of Defense.

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Authors and Affiliations

  1. Department of Surgery, Center for Prostate Disease Research (CPDR), Uniformed Services University, Rockville, MD, USA

    C Sun, Y Shi, L L Xu, C Nageswararao, L D Davis, T Segawa, A Dobi, D G McLeod & S Srivastava

  2. Urology Service, Walter Reed Army Medical Center, Washington, DC, USA

    D G McLeod

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  1. C Sun
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Correspondence to S Srivastava.

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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc).

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Sun, C., Shi, Y., Xu, L. et al. Androgen receptor mutation (T877A) promotes prostate cancer cell growth and cell survival. Oncogene 25, 3905–3913 (2006). https://doi.org/10.1038/sj.onc.1209424

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