A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth

Zhiyong Guo, Xi Yang, Feng Sun, Richeng Jiang, Douglas E. Linn, Hege Chen, Hegang Chen, Xiangtian Kong, Jonathan Melamed, Clifford G. Tepper, Hsing Jien Kung, Angela M H Brodie, Joanne Edwards, Yun Qiu

Research output: Contribution to journalArticle

545 Citations (Scopus)

Abstract

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 up-regulated 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, whereas specific knockdown 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 the regulation of 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 antiandrogen drugs, development of new drugs targeting these AR isoforms may potentially be effective for treatment of ablation-resistant PCA.

Original languageEnglish
Pages (from-to)2305-2313
Number of pages9
JournalCancer Research
Volume69
Issue number6
DOIs
Publication statusPublished - Mar 15 2009
Externally publishedYes

Fingerprint

Androgen Receptors
Androgens
Prostatic Neoplasms
Growth
Androgen Antagonists
Prostate
Tissue Array Analysis
Hormones
Drug Delivery Systems
Prostatectomy
Heterografts
Protein Isoforms
Cell Culture Techniques
Immunohistochemistry
Ligands
Recurrence
Therapeutics
Pharmaceutical Preparations
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. / Guo, Zhiyong; Yang, Xi; Sun, Feng; Jiang, Richeng; Linn, Douglas E.; Chen, Hege; Chen, Hegang; Kong, Xiangtian; Melamed, Jonathan; Tepper, Clifford G.; Kung, Hsing Jien; Brodie, Angela M H; Edwards, Joanne; Qiu, Yun.

In: Cancer Research, Vol. 69, No. 6, 15.03.2009, p. 2305-2313.

Research output: Contribution to journalArticle

Guo, Z, Yang, X, Sun, F, Jiang, R, Linn, DE, Chen, H, Chen, H, Kong, X, Melamed, J, Tepper, CG, Kung, HJ, Brodie, AMH, Edwards, J & Qiu, Y 2009, 'A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth', Cancer Research, vol. 69, no. 6, pp. 2305-2313. https://doi.org/10.1158/0008-5472.CAN-08-3795
Guo, Zhiyong ; Yang, Xi ; Sun, Feng ; Jiang, Richeng ; Linn, Douglas E. ; Chen, Hege ; Chen, Hegang ; Kong, Xiangtian ; Melamed, Jonathan ; Tepper, Clifford G. ; Kung, Hsing Jien ; Brodie, Angela M H ; Edwards, Joanne ; Qiu, Yun. / A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. In: Cancer Research. 2009 ; Vol. 69, No. 6. pp. 2305-2313.
@article{90b4a467374c4bd9b40ad5d984fa9b17,
title = "A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth",
abstract = "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 up-regulated 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, whereas specific knockdown 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 the regulation of 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 antiandrogen drugs, development of new drugs targeting these AR isoforms may potentially be effective for treatment of ablation-resistant PCA.",
author = "Zhiyong Guo and Xi Yang and Feng Sun and Richeng Jiang and Linn, {Douglas E.} and Hege Chen and Hegang Chen and Xiangtian Kong and Jonathan Melamed and Tepper, {Clifford G.} and Kung, {Hsing Jien} and Brodie, {Angela M H} and Joanne Edwards and Yun Qiu",
year = "2009",
month = "3",
day = "15",
doi = "10.1158/0008-5472.CAN-08-3795",
language = "English",
volume = "69",
pages = "2305--2313",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "6",

}

TY - JOUR

T1 - A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth

AU - Guo, Zhiyong

AU - Yang, Xi

AU - Sun, Feng

AU - Jiang, Richeng

AU - Linn, Douglas E.

AU - Chen, Hege

AU - Chen, Hegang

AU - Kong, Xiangtian

AU - Melamed, Jonathan

AU - Tepper, Clifford G.

AU - Kung, Hsing Jien

AU - Brodie, Angela M H

AU - Edwards, Joanne

AU - Qiu, Yun

PY - 2009/3/15

Y1 - 2009/3/15

N2 - 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 up-regulated 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, whereas specific knockdown 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 the regulation of 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 antiandrogen drugs, development of new drugs targeting these AR isoforms may potentially be effective for treatment of ablation-resistant PCA.

AB - 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 up-regulated 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, whereas specific knockdown 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 the regulation of 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 antiandrogen drugs, development of new drugs targeting these AR isoforms may potentially be effective for treatment of ablation-resistant PCA.

UR - http://www.scopus.com/inward/record.url?scp=65549168746&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=65549168746&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-08-3795

DO - 10.1158/0008-5472.CAN-08-3795

M3 - Article

VL - 69

SP - 2305

EP - 2313

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 6

ER -