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 5

ARv567es increases endogenous ARfl expression and activity to similar levels as overexpression of ARfl in LNCaP cells.

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ARv567es increases endogenous ARfl expression and activity to similar le...
(A) Western blot of LNCaP cells transfected with empty vector, ARfl, or ARv567es. Immunoblot with AR C-19 antibody, which only detects ARfl. Note the increase in ARfl following transfection with either ARfl or ARv567es compared with empty vector control. The panel on the right shows immunoblot using AR sc441 antibody to demonstrate presence of ARv567es in LNCaP ARv567es cells. The graph depicts relative amounts of ARfl present, using LNCaP pc plus DHT as the baseline. Values are mean ± SEM. (B) ARR3-Luc reporter assay on cell lines from A, grown with and without DHT (10–9 M). Note that for the LNCaP pc cells, DHT resulted in more than a 10-fold increase (P < 0.01) in reporter activity compared with baseline. This increase in activity is difficult to discern in this figure due to the scale used to show changes with the ARv567es construct. Values are mean ± SEM. *P < 0.01, LNCaP ARfl cells compared with LNCaP control cells with same treatment; **P < 0.001, LNCaP ARv567es cells compared with LNCaP ARfl cells with same treatment.