title: Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor.
abstract: Androgen receptor (AR) splice variants lacking the ligand binding domain (ARVs), originally isolated from prostate cancer cell lines derived from a single patient, are detected in normal and malignant human prostate tissue, with the highest levels observed in late stage, castration-resistant prostate cancer. The most studied variant (called AR-V7 or AR3) activates AR reporter genes in the absence of ligand and therefore, could play a role in castration resistance. To explore the range of potential ARVs, we screened additional human and murine prostate cancer models using conventional and next generation sequencing technologies and detected several structurally diverse AR isoforms. Some, like AR-V7/AR3, display gain of function, whereas others have dominant interfering activity. We also find that ARV expression increases acutely in response to androgen withdrawal, is suppressed by testosterone, and in some models, is coupled to full-length AR (AR-FL) mRNA production. As expected, constitutively active, ligand-independent ARVs such as AR-V7/AR3 are sufficient to confer anchorage-independent (in vitro) and castration-resistant (in vivo) growth. Surprisingly, this growth is blocked by ligand binding domain-targeted antiandrogens, such as MDV3100, or by selective siRNA silencing of AR-FL, indicating that the growth-promoting effects of ARVs are mediated through AR-FL. These data indicate that the increase in ARV expression in castrate-resistant prostate cancer is an acute response to castration rather than clonal expansion of castration or antiandrogen-resistant cells expressing gain of function ARVs, and furthermore, they provide a strategy to overcome ARV function in the clinic.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Watson
authors.forename: Yinan F
authors.initials: YF
authors.lastname: Chen
authors.forename: Minna D
authors.initials: MD
authors.lastname: Balbas
authors.forename: John
authors.initials: J
authors.lastname: Wongvipat
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Socci
authors.forename: Agnes
authors.initials: A
authors.lastname: Viale
authors.forename: Kwanghee
authors.initials: K
authors.lastname: Kim
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D059002:Androgen Receptor Antagonists; D000728:Androgens / Q000494:pharmacology; D000818:Animals; D002369:Castration; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005091:Exons / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism*; D020539:Sequence Analysis, Protein
chemical_list: D059002:Androgen Receptor Antagonists; D000728:Androgens; D012333:RNA, Messenger; D011944:Receptors, Androgen
references.citation: In Vivo. 2001 Mar-Apr;15(2):163-8
references.pmid: 11317522
references.citation: Cancer Res. 2002 Nov 15;62(22):6606-14
references.pmid: 12438256
references.citation: J Biol Chem. 2000 Jul 28;275(30):22986-94
references.pmid: 10816582
references.citation: Cancer Res. 1996 Jul 1;56(13):3042-6
references.pmid: 8674060
references.citation: J Biol Chem. 1994 May 6;269(18):13115-23
references.pmid: 8175737
references.citation: Cancer Res. 2009 Mar 15;69(6):2305-13
references.pmid: 19244107
references.citation: Mol Cell Endocrinol. 1992 Oct;88(1-3):153-64
references.pmid: 1334008
references.citation: Mol Cell Endocrinol. 2001 Jun 20;179(1-2):105-9
references.pmid: 11420135
references.citation: Nucl Recept Signal. 2008 Jun 27;6:e008
references.pmid: 18612376
references.citation: Cancer Res. 2005 Dec 15;65(24):11565-71
references.pmid: 16357166
references.citation: J Clin Oncol. 2005 Nov 10;23(32):8253-61
references.pmid: 16278481
references.citation: Cancer Res. 2008 Jul 1;68(13):5469-77
references.pmid: 18593950
references.citation: Cancer Lett. 2010 Feb 28;288(2):133-48
references.pmid: 19608332
references.citation: Science. 2009 May 8;324(5928):787-90
references.pmid: 19359544
references.citation: Cancer Res. 2004 Dec 15;64(24):8867-75
references.pmid: 15604246
references.citation: Mol Endocrinol. 1990 Jan;4(1):22-8
references.pmid: 2325667
references.citation: Lancet. 2010 Apr 24;375(9724):1437-46
references.pmid: 20398925
references.citation: Cancer Res. 2009 Jan 1;69(1):16-22
references.pmid: 19117982
references.citation: Biol Reprod. 1995 Sep;53(3):609-19
references.pmid: 7578685
references.citation: Bioinformatics. 2009 May 1;25(9):1105-11
references.pmid: 19289445
references.citation: Genes Dev. 2003 Dec 15;17(24):2998-3010
references.pmid: 14701871
references.citation: Adv Cancer Res. 2010;107:137-62
references.pmid: 20399963
references.citation: Biochem J. 1993 Aug 1;293 ( Pt 3):761-8
references.pmid: 8352744
references.citation: J Clin Invest. 2010 Aug;120(8):2715-30
references.pmid: 20644256
references.citation: Nucl Recept Signal. 2009 Jun 19;7:e007
references.pmid: 19636396
references.citation: Mol Endocrinol. 1993 Jul;7(7):924-36
references.pmid: 8413317
references.citation: Proc Natl Acad Sci U S A. 2005 Jul 12;102(28):9802-7
references.pmid: 15994236