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Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor.
Open accessAbstract
Androgen receptor (AR) splice variants lacking the ligand binding domain (ARVs), originally isolated from prostate cancer cell lines derived from a single patient, are detected in normal and malignant human prostate tissue, with the highest levels observed in late stage, castration-resistant prostate cancer. The most studied variant (called AR-V7 or AR3) activates AR reporter genes in the absence of ligand and therefore, could play a role in castration resistance. To explore the range of potential ARVs, we screened additional human and murine prostate cancer models using conventional and next generation sequencing technologies and detected several structurally diverse AR isoforms. Some, like AR-V7/AR3, display gain of function, whereas others have dominant interfering activity. We also find that ARV expression increases acutely in response to androgen withdrawal, is suppressed by testosterone, and in some models, is coupled to full-length AR (AR-FL) mRNA production. As expected, constitutively active, ligand-independent ARVs such as AR-V7/AR3 are sufficient to confer anchorage-independent (in vitro) and castration-resistant (in vivo) growth. Surprisingly, this growth is blocked by ligand binding domain-targeted antiandrogens, such as MDV3100, or by selective siRNA silencing of AR-FL, indicating that the growth-promoting effects of ARVs are mediated through AR-FL. These data indicate that the increase in ARV expression in castrate-resistant prostate cancer is an acute response to castration rather than clonal expansion of castration or antiandrogen-resistant cells expressing gain of function ARVs, and furthermore, they provide a strategy to overcome ARV function in the clinic.
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“The activity of these variants still depends on the presence of a full-length AR, although treatment with the AR antagonist MDV3100 or siRNA knockdown of full-length AR inhibited transcription and androgen-free growth (77).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [77]
In the citing paper
“Moreover, the constitutive activity attributed to some variants may still rely on the presence of the full-length AR to mediate binding of AR to DNA and stimulate transcription (77).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [77]
In the citing paper
“In one study, endogenous expression of variant mRNA in patient samples and xenografts is much lower (ϳ0.1-2.5%)relative to full-length AR mRNA (77).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [77]
In the citing paper
“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 [77]
In the citing paper
“Two such variants, human AR-V7, identified in CR prostate cancer specimens, and mouse AR-V4, from the murine Myc-CaP cell line, demonstrate ligand-free activation of a 4xARE-Luc promoter as well as promoting CR LNCaP tumor growth.”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [77]
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Cites
TopHat: discovering splice junctions with RNA-Seq
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Self-citationGuo, Z., Yang, X., Sun, F., Jiang, R., Linn, D. E., Chen, H., Chen, H., Kong, X., Melamed, J., Tepper, C. G., et al. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-3795 · Cited by 880
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Molecular basis of androgen insensitivity
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The Molecular Taxonomy of Primary Prostate Cancer
Abeshouse, A. A., Ahn, J., Akbani, R., Ally, A., Amin, S. B., Andry, C., Annala, M., Aprikian, A. G., Armenia, J., Arora, A., et al. (2015) · Cell · doi:10.1016/j.cell.2015.10.025 · Cited by 3,126
AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer
Antonarakis, E. S., Lu, C., Wang, H., Luber, B., Nakazawa, M., Roeser, J. C., Chen, Y., Mohammad, T. A., Chen, Y., Fedor, H. L., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1315815 · Cited by 2,710
Self-citationEmerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer
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Self-citationPROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer
Raina, K., Lu, J., Qian, Y., Altieri, M., Gordon, D., Rossi, A. M. K., Wang, J., Chen, X., Dong, H., Siu, K., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1521738113 · Cited by 852
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Metadata
- Authors
- Watson, P. A., Chen, Y. F., Balbas, M. D., Wongvipat, J., Socci, N. D., Viale, A., Kim, K., & Sawyers, C. L.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Human Oncology and Pathogenesis Program,
- Bioinformatics Core,
- University of California, Los Angeles (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Sawyers, Charles L.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-09-07
- Volume
- 107
- Issue
- 39
- Pages
- 16759-16765
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2947883
- OpenAlex
- W2083926838
- Cited by
- 639
- References
- 27
- Citations by year
- 2026: 8 · 2025: 19 · 2024: 22 · 2023: 33 · 2022: 25 · 2021: 26 · 2020: 43 · 2019: 33 · 2018: 36 · 2017: 43 · 2016: 63 · 2015: 48 · 2014: 64 · 2013: 65 · 2012: 53
- FWCI
- 46.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Prostate Cancer Foundation
- University of Washington
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Keywords
- androgen receptor splice variants, castration-resistant prostate cancer, AR-V7, ligand-independent receptor activation, full-length androgen receptor, androgen withdrawal, antiandrogen resistance, enzalutamide, anchorage-independent growth, siRNA knockdown, prostate cancer cell lines, androgen receptor isoforms
- MeSH terms
- Amino Acid Sequence, Androgens, Animals, Castration, Disease Models, Animal, Exons, Humans, Male, Molecular Sequence Data, Prostatic Neoplasms, Receptors, Androgen, RNA, Messenger, Gene Expression Regulation, Neoplastic, Alternative Splicing, Protein Structure, Tertiary, Sequence Analysis, Protein, Cell Line, Tumor, Mice, Androgen Receptor Antagonists
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