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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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 9

Expression profiles of LNCaP pc and LNCaP ARv567es cells.

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Expression profiles of LNCaP pc and LNCaP ARv567es cells. (A) Venn d...
(A) Venn diagrams showing the gene number per comparison for expression profiles of androgen-regulated and ARv567es-regulated genes in LNCaP cell lines. Cells were grown in CS medium with or without DHT (10–9 M) for 24 hours, in triplicate experiments. Microarray analysis using Agilent 44K whole human genome expression oligonucleotide microarray slides was performed. Statistical analysis was conducted using 2-sample, unpaired t test with the SAM software, with a q value of less than 0.01% considered statistically significant for ARfl cells and a q value of less than 10% considered statistically significant for ARv567es cells. I and IV indicate genes upregulated or downregulated by DHT in LNCaP cells; II and V indicate genes upregulated or downregulated by DHT in LNCaP cells or LNCaP ARv567es cells compared with LNCaP cells with no DHT; and III and VI indicate genes regulated by ARv567es in LNCaP cells compared with LNCaP cells without DHT. (B) The top AR-regulated genes in the LNCaP ARv567es cells compared with LNCaP controls grown in CS medium. Note that the right hand column shows changes in genes previously described to be regulated by DHT in LNCaP cells. Results of GO analysis of genes upregulated or downregulated by DHT in AR cells or genes uniquely upregulated or downregulated in ARv567es cells are listed in Supplemental Tables 2 and 3.