A Novel Androgen Receptor Splice Variant Is Upregulated during Prostate Cancer Progression and Promotes Androgen-depletion-resistant Growth

By Zhiyong Guo, Xi Yang, F. Sun, R. Jiang, Douglas E. Linn, Hege Chen, Hegang Chen, X. Kong, J. Melamed, C. Tepper and 4 more. Cancer Research, 2009

889 citations recorded by the source corpus.

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 upregulated 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 while specific knock-down 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 regulating 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 anti-androgen drugs, development of new drugs targeting these AR isoforms may potentially be effective for treatment of ablation-resistant PCA.

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

View Paper: https://www.semanticscholar.org/paper/ae9b795672757f60aa3d57c603a47a35322742e5

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Endocrinology, Diabetes and Metabolism

1. John Wongvipat
2. C. Sawyers

In Genetics

1. John Wongvipat
2. Nicholas D. Socci
3. C. Sawyers
4. P. Keeling

In Pulmonary and Respiratory Medicine

1. John Wongvipat
2. Philip A Watson
3. R. Vessella
4. C. Sawyers

Citations in the corpus

• Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines (2012, background): “Therefore, we conclude that the 48-kb AR intron 1 deletion can discriminate between individual cells in the heterogeneous CWR-R1 cell line that are enzalutamide-responsive and cells that are driven by AR-V activity and resistant to inhibition of full-length AR. AR-Vs are independent effectors of the”
• Association of AR-V7 on Circulating Tumor Cells as a Treatment-Specific Biomarker With Outcomes and Survival in Castration-Resistant Prostate Cancer (2016, neutral): “Blood age, median (range), h 25 (2-78) 27 (1-51) .”
• 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).”
• Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor (2010, positive): “As expected, constitutively active, ligand-independent ARVs such as AR-V7/AR3 are sufficient to confer anchorage-independent (in vitro) and castrationresistant (in vivo) growth.”
• Resistance to CYP17A1 inhibition with abiraterone in castration resistant prostate cancer: Induction of steroidogenesis and androgen receptor splice variants (2011, positive): “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).”