Ligand-independent Androgen Receptor Variants Derived from Splicing of Cryptic Exons Signify Hormone Refractory Prostate Cancer

By R. Hu, T. Dunn, Shuanzeng Wei, S. Isharwal, R. Veltri, E. Humphreys, Misop Han, Alan W. Partin, R. Vessella, W. Isaacs and 2 more. Cancer Research, 2009

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Suppression of androgen production and function provides palliation but not cure in men with prostate cancer (PCa). Therapeutic failure and progression to hormone refractory prostate cancer (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 7 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 demonstrated an average 20-fold higher expression in HRPC (n=25) when compared to hormone naïve PCa (n=82) (p<0.0001). Among the hormone naïve 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 naïve 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.

Subfields: Endocrinology, Diabetes and Metabolism, Genetics, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/6f5e350ad4c25053f24e82433ba556c36111181f

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Citations in the corpus

Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines (2012, methodology): “Cells were electroporated with siRNAs targeted to AR Exon 7 (15), AR Exon 1 (15), AR Exon 2b (15), AR Exon CE3 (10), or an MMTV-LUC reporter as described (15).”
Liquid biopsy: a step closer to transform diagnosis, prognosis and future of cancer treatments (2022, background): “The ligand-independent AR-V7 variant, thus, results in a subsequent upregulation of AR modulated genes [56].”
Molecular genetics of prostate cancer: new prospects for old challenges. (2010, background): “In addition, recent studies have shown that expression of alternative splice isoforms encoding constitutively active AR variants also occurs in castration-resistant cancer (Dehm et al. 2008; Guo et al. 2009; Hu et al. 2009).”