Recent Advances in Androgen-Receptor Splicing Variants Related to the Mechanism and Treatment of Castration-Resistant Prostate Cancer

Author(s): Jianguo Liao, Wenhai Pan

Prostate cancer is one of the most common malignant solid tumors in men. In the United States in 2020, prostate cancer is predicted to cause 191930 new cases, accounting for 21% of the total number of new solid tumors in all men. [1] China and Asia faster-growing incidence of prostate cancer (PCa), [2] The death rate from prostate cancer in urban areas of mainland China increased by nearly 50% in 2009, compared with 2004.

1. Siegel RL, Miller KD, Jemal A Cancer statistics, 2020.CA Cancer J Clin. 2020 Jan;70(1):7-30. doi: 10.3322/caac.21590. Epub 2020 Jan 8.
2. YANG Jinyi ,YANG Mingzhoum WEI Weim ,YUE Wenchang . Epidemiological study on the occurrence and development of prostate cancer .Journal of Clinical Urology ,DOI 10.13201/j.issn.1001-1420.2017.09.018
3. Ye Dingwei, Zhu Yao. Epidemiology of prostate cancer in China： an overview and clinical implication．Chinese Journal of Surgery，DOI 10.3760/cma.j.issn.0529-5815.2015.04.003
4. HAN Sujun, ZHANG Siwei, et al. Analysis of the status and trends of prostate cancer incidence in China .Chinese Clinical Oncology,DOI 10.3969/j.issn.1009-0460.2013.04.009
5. Chinese Anticancer Association Genitourinary Oncology Committee .Chinese experts consensus on the treatment of metastatic prostate cancer 2018 edition , Chinese Journal of Surgery, DOI 10.3760/cma.j.issn.0529-5815.2018.09.002
6. ZENG Hao , CHONG Tie ,et al. Assessment of updated guidelines for castration-resistant prostate cancer—Western China expert consensus conference ,Journal of Modern Urology, DOI10.3969/j.issn.1009-8291.2017.02.002
7. Li H, Wang Z, Xiao W, Yan L, Guan W, Hu Z, et al. Androgenreceptor splice variant-7-positive prostate cancer: a novel molecular subtype with markedly worse androgen-deprivation therapy outcomes in newly diagnosed patients. Mod Pathol 2018;31:198-208.
8. CornfordP, BellmuntJ, BollaM, BriersE.EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part II: Treatment of Relapsing, Metastatic, and Castration-Resistant Prostate Cancer.Eur Urol. 2017 Apr;71(4):630-642
9. RASSO CS，wu YM，ROBINSON DR，et a1．The mutational landscape of lethal castration—resistant prostate cancer．Nature，2012，487(7406)：239-243．
10. Centenera MM, Harris JM, Tilley WD, Butler LM.The contribution of different androgen receptor domainsto receptor dimerization and signaling.Mol Endocrinol. 2008 Nov;22(11):2373-82
11. Narayanan R, Coss CC, Dalton JT.Development of selective androgen receptor modulators (SARMs).Mol Cell Endocrinol. 2018 Apr 15;465:134-142.
12. Philip A. Watson,Yinan F. Chen,Minna D. Balbas,John Wongvipat,Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptorProc Natl Acad Sci U S A. 2010 Sep 28; 107(39): 16759–16765.
13. Shafi AA, Yen AE, Weigel NL.Androgen receptors in hormone-dependent and castration-resistant prostate cancer.Pharmacol Ther. 2013 Dec;140(3):223-38.
14. Rong Hu, Changxue Lu, Elahe A. Mostaghel, Distinct transcriptional programs mediated by the ligand-dependent full-length androgen receptor and its splice variants in castration-resistant prostate cancer . Cancer Res. 2012 Jul 15; 72(14): 3457–3462.
15. Zhang X, Morrissey C, Sun S, Ketchandji M, et al.
16. Androgen receptor variants occur frequently in castration resistant prostate cancer metastases.PLoS One. 2011;6(11):e27970.
17. Ciccarese C, Santoni M, Brunelli M, et al.
18. AR-V7 and prostate cancer: The watershed for treatment selection?Cancer Treat Rev. 2016 Feb;43:27-35.
19. Paschalis A, Sharp A, Welti JC, Neeb A, et al.Alternative splicing in prostate cancer.Nat Rev Clin Oncol.
20. 2018 Nov;15(11):663-675.
21. Watson PA, Chen YF, Balbas MD, Wongvipat J, et al.Constitutively active androgen
22. receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor.Proc Natl Acad Sci U S A. 2010 Sep 28;107(39):16759-65.
23. HörnbergE ，Ylitalo EB, Crnalic S, et al. Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival. PLoS ONE 2011;6:e19059.
24. Liu G, Sprenger C, Sun S, Epilepsia KS, Haugk K, et al.AR variant ARv567es induces carcinogenesis in a novel transgenic mouse model of prostatecancer.Neoplasia. 2013 Sep;15(9):1009-17.
25. chongfuThadani-Mulero M, Portella L, Sun S, Sung M, Matov A, Vessella RL, et al. Androgen receptor splice variants determine taxane sensitivity in prostate cancer. Cancer Res 2014;74:2270–82.
26. Sun S, Sprenger CC, Vessella RL, et al. Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Invest 2010;120:2715–30
27. Guo Z, Yang X, Sun F, Jiang R, Linn DE,.A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth.Cancer Res. 2009 Mar 15;69(6):2305-2313.
28. Liu LL, Xie N, Sun S, Plymate S, et al.Mechanisms of the androgen receptor splicing in prostate cancer cells.Oncogene. 2014 Jun 12;33(24):3140-50.
29. Sun F, Chen HG, Li W, Yang X, Wang X, Jiang R..Androgen receptor splice variant AR3 promotes prostate cancer via modulating expression of autocrine/paracrine factors.J Biol Chem. 2014 Jan 17;289(3):1529-39.
30. Ziyang Yu, Sen Chen, Adam G. Sowalsky, et al.Rapid Induction of Androgen Receptor Splice Variants by Androgen Deprivation in Prostate CancerClin Cancer Res. 2014 Mar 15; 20(6): 1590–1600.
31. Hu R, Dunn TA, Wei S, et al. Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res 2009;69:16-22.
32. Yingming Li, Siu Chiu Chan,et al.Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines Cancer Res. 2013 Jan 15; 73(2): 483–489.
33. Scher HI, Lu D, Schreiber NA, et al. Association of AR-V7 on Circulating Tumor Cells as a Treatment-Specific Biomarker With Outcomes and Survival in Castration-Resistant Prostate Cancer.JAMA Oncol. 2016 Nov 1;2(11):1441-1449
34. Seitz AK, Thoene S, Bietenbeck A, et al.
35. AR-V7 in Peripheral Whole Blood of Patients with Castration-resistant Prostate Cancer: Association with Treatment-specific Outcome Under Abiraterone and Enzalutamide.Eur Urol. 2017 Nov;72(5):828-834
36. Sharp A, Coleman I, Yuan W, et al.Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer.J Clin Invest. 2019 Jan 2;129(1):192-208.
37. Mostaghel EA, Marck BT, Plymate SR, et al.
38. Resistance to CYP17A1 inhibition with abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and androgen receptor splice variants.Clin Cancer Res. 2011 Sep 15;17(18):5913-25
39. Nakazawa M, Lu C, Chen Y, Paller CJ, Carducci MA, Eisenberger MA, et al. Serial blood-based analysis of AR-V7 in men with advanced prostate cancer. Ann Oncol 2015;26:1859-65.
40. Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014;371:1028–3
41. Antonarakis ES, Lu C, Luber B, Wang H, Chen Y, Nakazawa M, et al. Androgen receptor splice variant 7 and efficacy of taxane chemotherapy in patients with metastatic castrationresistant prostate cancer. JAMA Oncol 2015;1:582-91.
42. Ahrens-Fath I1, Politz O, Geserick C, Haendler B. Androgen receptor function is modulated by the tissue-specific AR45 variant.FEBS J. 2005 Jan;272(1):74-84.
43. Rong Hu, William B. Isaacs, and Jun Luo1,A Snapshot of the Expression Signature of Androgen Receptor Splicing Variants and Their Distinctive Transcriptional Activities Prostate. 2011 Nov; 71(15): 1656–1667.
44. Yang X, Guo Z, Sun F, et al. Novel membrane-associated androgen receptor splice variant potentiates proliferative and survival responses in prostate cancer cells. J Biol Chem 2011;286:36152-60
45. Dehm SM, Tindall DJ. Alternatively spliced androgen receptor variants. Endocr Relat Cancer 2011;18:R183-96.