Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer.
Open accessPublished version of a preprint
Abstract
Suppression of androgen production and function provides palliation but not cure in men with prostate cancer (PCa). Therapeutic failure and progression to hormone-refractory PCa (HRPC) are often accompanied by molecular alterations involving the androgen receptor (AR). In this study, we report novel forms of AR alteration that are prevalent in HRPC. Through in silico sequence analysis and subsequent experimental validation studies, we uncovered seven AR variant transcripts lacking the reading frames for the ligand-binding domain due to splicing of "intronic" cryptic exons to the upstream exons encoding the AR DNA-binding domain. We focused on the two most abundantly expressed variants, AR-V1 and AR-V7, for more detailed analysis. AR-V1 and AR-V7 mRNA showed an average 20-fold higher expression in HRPC (n = 25) when compared with hormone-naive PCa (n = 82; P < 0.0001). Among the hormone-naive PCa, higher expression of AR-V7 predicted biochemical recurrence following surgical treatment (P = 0.012). Polyclonal antibodies specific to AR-V7 detected the AR-V7 protein frequently in HRPC specimens but rarely in hormone-naive PCa specimens. AR-V7 was localized in the nuclei of cultured PCa cells under androgen-depleted conditions, and constitutively active in driving the expression of canonical androgen-responsive genes, as revealed by both AR reporter assays and expression microarray analysis. These results suggest a novel mechanism for the development of HRPC that warrants further investigation. In addition, as expression markers for lethal PCa, these novel AR variants may be explored as potential biomarkers and therapeutic targets for advanced PCa.
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When ectopically expressed in PC-3 cells, the AR-V7 variant is localized in the nuclei and is constitutively active in the absence of androgen.
“When ectopically expressed in PC-3 cells, the AR-V7 variant is localized in the nuclei and is constitutively active in the absence of androgen (75).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [75]
Early evidence suggests that expression of some androgen receptor variant in prostate tumors is associated with poor clinical outcome.
“Early evidence suggests that expression of some AR variant in prostate tumors is associated with poor clinical outcome (75).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [75]
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- Authors
- Hu, R., Dunn, T. A., Wei, S., Isharwal, S., Veltri, R. W., Humphreys, E., Han, M., Partin, A. W., Vessella, R. L., Isaacs, W. B., Bova, G. S., & Luo, J.
- Affiliations
- 1Urology, Departments of
- Johns Hopkins University (US)
- University of Washington (US)
- ORCID
- Venue
- Cancer Research
- Published
- 2008-12-31
- Volume
- 69
- Issue
- 1
- Pages
- 16-22
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC2614301
- OpenAlex
- W2097226696
- Cited by
- 1,077
- References
- 20
- Citations by year
- 2026: 22 · 2025: 24 · 2024: 40 · 2023: 52 · 2022: 80 · 2021: 71 · 2020: 74 · 2019: 67 · 2018: 74 · 2017: 70 · 2016: 110 · 2015: 75 · 2014: 67 · 2013: 89 · 2012: 53
- FWCI
- 33.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P50CA058236, P50-CA58236)
- 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 › Pulmonary and Respiratory Medicine › Prostate Cancer Diagnosis and Treatment
- Keywords
- androgen receptor, castration-resistant prostate cancer, cryptic exons, alternative splicing, AR-V7, ligand-independent receptor activation, androgen receptor variants, biochemical recurrence, prognostic factors, therapeutic target
- MeSH terms
- Cloning, Molecular, Exons, Humans, Ligands, Male, Neoplasms, Hormone-Dependent, Prostatic Neoplasms, Receptors, Androgen, Protein Biosynthesis, Open Reading Frames, Alternative Splicing, Protein Isoforms
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