Splicing of a novel AR exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance

By S. Dehm, L. Schmidt, Hannelore V. Heemers, R. Vessella, D. Tindall. Cancer Research, 2008

807 citations recorded by the source corpus.

The standard systemic treatment for prostate cancer (PCa) is androgen ablation, which causes tumor regression by inhibiting activity of the androgen receptor (AR). Invariably, PCa recurs with a fatal androgen-refractory phenotype. Importantly, the growth of androgen-refractory PCa remains dependent on the AR through various mechanisms of aberrant AR activation. Here we studied the 22Rv1 PCa cell line, which was derived from a CWR22 xenograft that relapsed during androgen ablation. Three AR isoforms are expressed in 22Rv1 cells: a full-length version with duplicated Exon 3, and two truncated versions lacking the COOH-terminal domain (CTD). We found that CTD-truncated AR isoforms are encoded by mRNAs that have a novel Exon 2b at their 3′ end. Functionally, these AR isoforms are constitutively active, and promote the expression of endogenous AR-dependent genes as well as the proliferation of 22Rv1 cells in a ligand-independent manner. AR mRNAs containing Exon 2b and their protein products are expressed in commonly studied PCa cell lines. Moreover, Exon 2b-derived species are enriched in xenograft-based models of therapy-resistant PCa. Together, our data describe a simple and effective mechanism by which PCa cells can synthesize a constitutively active AR, and thus circumvent androgen ablation.

Subfields: Molecular Biology, Pulmonary and Respiratory Medicine, Spectroscopy

View Paper: https://www.semanticscholar.org/paper/ce26578129f8ba4e87451c07d2bcb36445415c30

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Citations in the corpus

A Novel Androgen Receptor Splice Variant Is Upregulated during Prostate Cancer Progression and Promotes Androgen-depletion-resistant Growth (2009, background): “During the preparation of this manuscript, two AR variants expressed in 22Rv1 cells were reported recently (31).”
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).”
The molecular taxonomy of primary prostate cancer (2015, background): “…output is a proxy for ligand-driven AR activity in many tumors, AR transcript variants have been described that encode truncated AR proteins that lack the ligand-binding domain and hence are capable of activating AR target genes in the absence of androgens (Dehm et al., 2008, Watson et al., 2010).”
Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines (2012, methodology): “Fold change in mRNA expression levels was calculated by the comparative Ct method, using the formula 2 (DDCt) and GAPDH as calibrator, as described previously (15).”
Translating RNA sequencing into clinical diagnostics: opportunities and challenges (2016, background): “For example, expression of the alternatively spliced androgen receptor variant 7 (AR-V7) has been detected in the circulating tumour cells of ~30% of men with castrationresistant prostate cancer and is associated with reduced response to androgen receptor-directed therapies 31, 32 .”
Resistance to CYP17A1 inhibition with abiraterone in castration resistant prostate cancer: Induction of steroidogenesis and androgen receptor splice variants (2011, neutral): “Castration resistant prostate tumors frequently express elevated levels of full-length AR (AR) and, as recently reported, increases in expression of AR splice variants that confer constitutive ligand-independent activity (2, 7-11)(12).”