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

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

doi:10.1172/jci41824

Cited by 748Prostate Cancer Treatment and ResearchChromatin Remodeling and CancerSperm and Testicular Function

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

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Sun, Shihua, Sprenger, Cynthia C.T., Vessella, Robert L., Haugk, Kathleen, Soriano, Kathryn, Mostaghel, Elahe A., Page, Stephanie T., Coleman, Ilsa M. +4 more·2010·Journal of Clinical Investigation

DOI 10.1172/jci41824PMC PMC2912187

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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.

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Comparison of the transcriptome of androgen receptor variants with that of full-length AR suggests a significant amount of target specificity for each variant.
“Interestingly, comparison of the transcriptome of variants with that of full-length AR suggests a significant amount of target specificity for each variant (76 -78).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [76]
Another study found expression of variant protein AR v567es to be significantly higher in two of three LuCaP xenografts examined.
“In contrast, another study found the expression of variant protein (AR v567es ) to be significantly higher in two of three LuCaP xenografts examined, and variant mRNA of any form increased in CR patient metastases (41 of 69) compared with normal tissue samples (10 of 36) (76).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [76]
Variant mRNA of any form increased in castration-recurrent patient metastases (41 of 69) compared with normal tissue samples (10 of 36).
“In contrast, another study found the expression of variant protein (AR v567es ) to be significantly higher in two of three LuCaP xenografts examined, and variant mRNA of any form increased in CR patient metastases (41 of 69) compared with normal tissue samples (10 of 36) (76).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [76]
Full-length androgen receptor and the AR v567es variant do interact when coexpressed in AR-null prostate cancer cells.
“Full-length AR and the AR v567es variant do interact when coexpressed in AR-null prostate cancer cells (76).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [76]

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Huggins C, Hodges C. Studies on prostate cancer: effect of castration, estrogen, and androgen injec- tion on serum phosphatases in metastatic carci- noma of the prostate. Cancer Res. 1941;1:293-297.

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Authors: Sun, S., Sprenger, C. C. T., Vessella, R. L., Haugk, K., Soriano, K., Mostaghel, E. A., Page, S. T., Coleman, I. M., Nguyen, H. M., Sun, H., Nelson, P. S., & Plymate, S. R.
Affiliations: University of Washington (US)
VA Puget Sound Health Care System (US)
Fred Hutch Cancer Center (US)
Baylor College of Medicine (US)
Corresponding author: Plymate, Stephen R.
ORCID: Sun, Shihua
Sprenger, Cynthia C.T.
Mostaghel, Elahe A.
Page, Stephanie T.
Coleman, Ilsa M.
Nguyen, Holly M.
Sun, Huiying
Nelson, Peter S.
Plymate, Stephen R.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2010-08-02
Volume: 120
Issue: 8
Pages: 2715-2730
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci41824
PMC: PMC2912187
OpenAlex: W1975609403
Cited by: 748
References: 53
Citations by year: 2026: 11 · 2025: 13 · 2024: 26 · 2023: 46 · 2022: 35 · 2021: 42 · 2020: 38 · 2019: 40 · 2018: 48 · 2017: 58 · 2016: 76 · 2015: 62 · 2014: 65 · 2013: 84 · 2012: 49
FWCI: 49.34
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: U.S. Department of Veterans Affairs
University of Washington
National Institutes of Health
National Institute on Aging (K23AG027238)
National Cancer Institute (P01CA085859, P50CA097186)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
Keywords: castration-resistant prostate cancer, androgen receptor, splice variants, constitutively active receptor, androgen receptor blockade, prostate cancer metastasis, xenograft models, biomarkers, androgen receptor transcriptional activity
MeSH terms: Vorinostat, Androgen Antagonists, Animals, Humans, Hydroxamic Acids, Male, Neoplasm Metastasis, Neoplasm Transplantation, Orchiectomy, Prostatic Neoplasms, Receptors, Androgen, RNA Splicing, Transplantation, Heterologous, Gene Expression Regulation, Neoplastic, Cell Line, Tumor, Mice

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

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