A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth
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Abstract
The androgen receptor (AR) plays a key role in progression to incurable androgen ablation–resistant prostate cancer (PCA). We have identified three novel AR splice variants lacking the ligand-binding domain (designated as AR3, AR4, and AR5) in hormone-insensitive PCA cells. AR3, one of the major splice variants expressed in human prostate tissues, is constitutively active, and its transcriptional activity is not regulated by androgens or antiandrogens. Immunohistochemistry analysis on tissue microarrays containing 429 human prostate tissue samples shows that AR3 is significantly up-regulated during PCA progression and AR3 expression level is correlated with the risk of tumor recurrence after radical prostatectomy. Overexpression of AR3 confers ablation-independent growth of PCA cells, whereas specific knockdown of AR3 expression (without altering AR level) in hormone-resistant PCA cells attenuates their growth under androgen-depleted conditions in both cell culture and xenograft models, suggesting an indispensable role of AR3 in ablation-independent growth of PCA cells. Furthermore, AR3 may play a distinct, yet essential, role in ablation-independent growth through the regulation of a unique set of genes, including AKT1, which are not regulated by the prototype AR. Our data suggest that aberrant expression of AR splice variants may be a novel mechanism underlying ablation independence during PCA progression, and AR3 may serve as a prognostic marker to predict patient outcome in response to hormonal therapy. Given that these novel AR splice variants are not inhibited by currently available antiandrogen drugs, development of new drugs targeting these AR isoforms may potentially be effective for treatment of ablation-resistant PCA. [Cancer Res 2009;69(6):2305–13]
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AR mutants lacking AF-2 or splicing variants lacking the LBD still have potent transcription activation.
“AF-2 deletion mutants of AR or AR splicing variants lacking LBD still possess potent transcription activation functions (Guo et al., 2009; Jenster et al., 1995; Jenster et al., 1991; Simental et al., 1991).”
From Structural Insights of Transcriptionally Active, Full-Length Androgen Receptor Coactivator Complexes (2020) · cites this paper as Guo et al., 2009
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 [78]
At least in the CWR22R xenograft model, heterodimers of full-length androgen receptor with variants were not found by coimmunoprecipitation.
“At least in the CWR22R xenograft model, heterodimers of full-length AR with variants was not found by coimmunoprecipitation (78).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [78]
Localization of AR-V7 is cytoplasmic in many benign and androgen-dependent tissues but is found in the nucleus in castration-recurrent tumors.
“Localization of AR-V7 is cytoplasmic in many benign and AD tissues but is found in the nucleus in CR tumors (78).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [78]
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- Authors
- Guo, Z., Yang, X., Sun, F., Jiang, R., Linn, D. E., Chen, H., Chen, H., Kong, X., Melamed, J., Tepper, C. G., Kung, H.-J., Brodie, A. M. H., Edwards, J., & Qiu, Y.
- Affiliations
- University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center (US)
- University of Maryland, Baltimore (US)
- New York University (US)
- UC Davis Comprehensive Cancer Center (US)
- Glasgow Royal Infirmary (GB)
- ORCID
- Venue
- Cancer Research
- Published
- 2009-03-15
- Volume
- 69
- Issue
- 6
- Pages
- 2305-2313
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC2672822
- OpenAlex
- W2149131962
- Cited by
- 880
- References
- 45
- Citations by year
- 2026: 18 · 2025: 25 · 2024: 29 · 2023: 41 · 2022: 40 · 2021: 53 · 2020: 45 · 2019: 54 · 2018: 55 · 2017: 70 · 2016: 90 · 2015: 62 · 2014: 70 · 2013: 82 · 2012: 52
- FWCI
- 40.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Funders
- U.S. Department of Defense (W81XWH, CA106504)
- National Institutes of Health (W81XWH)
- National Cancer Institute (CA106504, R01CA106504, UO1-CA86772, U01CA086772)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Diagnosis and Treatment
- Keywords
- androgen receptor, splice variants, Ar3+, androgen ablation resistance, prostate cancer progression, androgen-independent growth, ligand-binding domain, AKT1, prognostic factors, antiandrogen resistance, hormone therapy response
- MeSH terms
- Androgens, Animals, Chlorocebus aethiops, Cloning, Molecular, Humans, Male, Neoplasm Recurrence, Local, Neoplasms, Hormone-Dependent, Prostatic Neoplasms, Receptors, Androgen, Up-Regulation, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Disease Progression, COS Cells, Protein Isoforms, Cell Line, Tumor, Cell Growth Processes, Proto-Oncogene Proteins c-akt
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