Rapid induction of androgen receptor splice variants by androgen deprivation in prostate cancer.
OBJECTIVE
Mechanisms mediating androgen receptor (AR) reactivation in prostate cancer that progresses after castration (castration-resistant prostate cancer; CRPC) and subsequent treatment with abiraterone (CYP17A1 inhibitor that further suppresses androgen synthesis) remain unclear.


METHODS
Prostate cancer xenografts were examined to identify mechanism of progression after castration and abiraterone.


RESULTS
AR reactivation in abiraterone-resistant VCaP xenografts was not associated with restoration of intratumoral androgens or alterations in AR coregulators. In contrast, mRNA encoding full-length AR (AR-FL) and a constitutively active splice variant (AR-V7) were increased compared with xenografts before castration, with an increase in AR-V7 relative to AR-FL. This shift toward AR-V7 was due to a feedback mechanism whereby the androgen-liganded AR stimulates expression of proteins that suppress generation of AR-V7 relative to AR-FL transcripts. However, despite the increases in AR-V7 mRNA, it remained a minor transcript (<1%) relative to AR-FL in resistant VCaP xenografts and CRPC clinical samples. AR-V7 protein expression was similarly low relative to AR-FL in castration-resistant VCaP xenografts and androgen-deprived VCaP cells, but the weak basal AR activity in these latter cells was further repressed by AR-V7 siRNA.


CONCLUSIONS
AR-V7 at these low levels is not adequate to restore AR activity, but its rapid induction after androgen deprivation allows tumors to retain basal AR activity that may be needed for survival until more potent mechanisms emerge to activate AR. Agents targeting AR splice variants may be most effective when used very early in conjunction with therapies targeting the AR ligand-binding domain.
Authors' Affiliations: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts; and Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington.
Ziyang
Z
Yu
Sen
S
Chen
Adam G
AG
Sowalsky
Olga S
OS
Voznesensky
Elahe A
EA
Mostaghel
Peter S
PS
Nelson
Changmeng
C
Cai
Steven P
SP
Balk
D017398:Alternative Splicing; D000726:Androgen Antagonists / Q000494:pharmacology*; D000736:Androstenes; D000737:Androstenols; D000818:Animals; D002369:Castration; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D000726:Androgen Antagonists; D000736:Androstenes; D000737:Androstenols; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; C089740:abiraterone