Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant
Shihua Sun, … , Peter S. Nelson, Stephen R. Plymate
Shihua Sun, … , Peter S. Nelson, Stephen R. Plymate
Published July 19, 2010
Citation Information: J Clin Invest. 2010;120(8):2715-2730. https://doi.org/10.1172/JCI41824.
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Research Article Oncology

Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant

Abstract

Progression of prostate cancer following castration is associated with increased androgen receptor (AR) expression and signaling despite AR blockade. Recent studies suggest that these activities are due to the generation of constitutively active AR splice variants, but the mechanisms by which these splice variants could mediate such effects are not fully understood. Here we have identified what we believe to be a novel human AR splice variant in which exons 5, 6, and 7 are deleted (ARv567es) and demonstrated that this variant can contribute to cancer progression in human prostate cancer xenograft models in mice following castration. We determined that, in human prostate cancer cell lines, ARv567es functioned as a constitutively active receptor, increased expression of full-length AR (ARfl), and enhanced the transcriptional activity of AR. In human xenografts, human prostate cancer cells transfected with ARv567es cDNA formed tumors that were resistant to castration. Furthermore, the ratio of ARv567es to ARfl expression within the xenografts positively correlated with resistance to castration. Importantly, we also detected ARv567es frequently in human prostate cancer metastases. In summary, these data indicate that constitutively active AR splice variants can contribute to the development of castration-resistant prostate cancers and may serve as biomarkers for patients who are likely to suffer from early recurrence and are candidates for therapies directly targeting the AR rather than ligand.

Authors

Shihua Sun, Cynthia C.T. Sprenger, Robert L. Vessella, Kathleen Haugk, Kathryn Soriano, Elahe A. Mostaghel, Stephanie T. Page, Ilsa M. Coleman, Holly M. Nguyen, Huiying Sun, Peter S. Nelson, Stephen R. Plymate

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Figure 1

Identification of a novel AR splice variant.

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Identification of a novel AR splice variant. (A) Agarose gels showing PC...
(A) Agarose gels showing PCR amplification of AR from human prostate LuCaP xenografts. Three sets of primers were used for PCR amplification of AR. One set is specific for exons 1–3 (amplicon 1), and another is specific for exons 2–8 (amplicon 2). The final set is specific for the 4–8 junction present in ARv567es (amplicon 3). Note that xenografts 86.2 and 136 have a smaller PCR product with the amplicon 2 primers, while several xenografts are positive for the deletion using the amplicon 3 primers. Inverted agarose images are shown. NTC, no template control. (B) A graph of relative amounts of ARv567es (amplicon 3) using qt-RT-PCR (mean ± 1 SD). Note that when xenografts occur as castrate-sensitive and castrate-resistant pairs (e.g., 35 and 35AI), the castrate-resistant sample (labeled AI) shows increased levels of ARv567es. The differences were significant at P < 0.05 for 35 versus 35AI and 96 versus 96AI.