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 11

Expression of the splice variant ARv567es in human prostates.

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Expression of the splice variant ARv567es in human prostates. (A) AR...
(A) AR variant PCR products from laser-captured samples of benign (B) and malignant tissue (T) from prostate tissue obtained at the time of prostatectomy from non-castrate men. Note that tumor or benign tissue may be positive in these samples. Samples 105–115 are PCR products from men, aged 35–55 years, with no evidence of prostate cancer, who were enrolled in a male contraception study. (B) Results of variant AR PCR products from metastases in a man who died from his prostate cancer. Table 1 shows results for all metastases samples. Variants include the ARv567es described in the current report and 2 variants previously described, AR3 and AR-V7. GAPDH was used as a control for adequacy of RNA in the sample. Primers are described in the Methods section. If GAPDH could not be amplified, the sample was not included in the study. Inverted agarose images are shown for A and B. (C) Diagram of ARv567es variant compared with previously published AR variants (AR1/2/2b in ref. 30; AR-V7 in ref. 14; and AR3 in ref. 13). RRP, radical retropubic prostatectomy.