Intragenic rearrangement and altered RNA splicing of the androgen receptor in a cell-based model of prostate cancer progression

Yingming Li, Majid Alsagabi, Danhua Fan, G. Steven Bova, Ahmed H. Tewfik, Scott M. Dehm

Research output: Contribution to journalArticle

Abstract

Androgen depletion for advanced prostate cancer (PCa) targets activity of the androgen receptor (AR), a steroid receptor transcription factor required for PCa growth. The emergence of lethal castration-resistant PCa (CRPCa) is marked by aberrant reactivation of the AR despite ongoing androgen depletion. Recently, alternative splicing has been described as a mechanism giving rise to COOH-terminally truncated, constitutively active AR isoforms that can support the CRPCa phenotype. However, the pathologic origin of these truncated AR isoforms is unknown. The goal of this study was to investigate alterations in AR expression arising in a cell-based model of PCa progression driven by truncated AR isoform activity. We show that stable, high-level expression of truncated AR isoforms in 22Rv1 CRPCa cells is associated with intragenic rearrangement of an approximately 35-kb AR genomic segment harboring a cluster of previously described alternative AR exons. Analysis of genomic data from clinical specimens indicated that related AR intragenic copy number alterations occurred in CRPCa in the context of AR amplification. Cloning of the break fusion junction in 22Rv1 cells revealed long interspersed nuclear elements (LINE-1) flanking the rearranged segment and a DNA repair signature consistent with microhomology-mediated, break-induced replication. This rearrangement served as a marker for the emergence of a rare subpopulation of CRPCa cells expressing high levels of truncated AR isoforms during PCa progression in vitro. Together, these data provide the first report of AR intragenic rearrangements in CRPCa and an association with pathologic expression of truncated AR isoforms in a cell-based model of PCa progression.

Original languageEnglish (US)
Pages (from-to)2108-2117
Number of pages10
JournalCancer Research
Volume71
Issue number6
DOIs
StatePublished - Mar 15 2011

Fingerprint

RNA Splicing
Androgen Receptors
Prostatic Neoplasms
Castration
Protein Isoforms
Androgens
Long Interspersed Nucleotide Elements
Steroid Receptors
Alternative Splicing
DNA Repair

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Intragenic rearrangement and altered RNA splicing of the androgen receptor in a cell-based model of prostate cancer progression. / Li, Yingming; Alsagabi, Majid; Fan, Danhua; Bova, G. Steven; Tewfik, Ahmed H.; Dehm, Scott M.

In: Cancer Research, Vol. 71, No. 6, 15.03.2011, p. 2108-2117.

Research output: Contribution to journalArticle

Li, Yingming ; Alsagabi, Majid ; Fan, Danhua ; Bova, G. Steven ; Tewfik, Ahmed H. ; Dehm, Scott M. / Intragenic rearrangement and altered RNA splicing of the androgen receptor in a cell-based model of prostate cancer progression. In: Cancer Research. 2011 ; Vol. 71, No. 6. pp. 2108-2117.
@article{b9ce1db1e22d484eae51045c7b6c8887,
title = "Intragenic rearrangement and altered RNA splicing of the androgen receptor in a cell-based model of prostate cancer progression",
abstract = "Androgen depletion for advanced prostate cancer (PCa) targets activity of the androgen receptor (AR), a steroid receptor transcription factor required for PCa growth. The emergence of lethal castration-resistant PCa (CRPCa) is marked by aberrant reactivation of the AR despite ongoing androgen depletion. Recently, alternative splicing has been described as a mechanism giving rise to COOH-terminally truncated, constitutively active AR isoforms that can support the CRPCa phenotype. However, the pathologic origin of these truncated AR isoforms is unknown. The goal of this study was to investigate alterations in AR expression arising in a cell-based model of PCa progression driven by truncated AR isoform activity. We show that stable, high-level expression of truncated AR isoforms in 22Rv1 CRPCa cells is associated with intragenic rearrangement of an approximately 35-kb AR genomic segment harboring a cluster of previously described alternative AR exons. Analysis of genomic data from clinical specimens indicated that related AR intragenic copy number alterations occurred in CRPCa in the context of AR amplification. Cloning of the break fusion junction in 22Rv1 cells revealed long interspersed nuclear elements (LINE-1) flanking the rearranged segment and a DNA repair signature consistent with microhomology-mediated, break-induced replication. This rearrangement served as a marker for the emergence of a rare subpopulation of CRPCa cells expressing high levels of truncated AR isoforms during PCa progression in vitro. Together, these data provide the first report of AR intragenic rearrangements in CRPCa and an association with pathologic expression of truncated AR isoforms in a cell-based model of PCa progression.",
author = "Yingming Li and Majid Alsagabi and Danhua Fan and Bova, {G. Steven} and Tewfik, {Ahmed H.} and Dehm, {Scott M.}",
year = "2011",
month = "3",
day = "15",
doi = "10.1158/0008-5472.CAN-10-1998",
language = "English (US)",
volume = "71",
pages = "2108--2117",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "6",

}

TY - JOUR

T1 - Intragenic rearrangement and altered RNA splicing of the androgen receptor in a cell-based model of prostate cancer progression

AU - Li, Yingming

AU - Alsagabi, Majid

AU - Fan, Danhua

AU - Bova, G. Steven

AU - Tewfik, Ahmed H.

AU - Dehm, Scott M.

PY - 2011/3/15

Y1 - 2011/3/15

N2 - Androgen depletion for advanced prostate cancer (PCa) targets activity of the androgen receptor (AR), a steroid receptor transcription factor required for PCa growth. The emergence of lethal castration-resistant PCa (CRPCa) is marked by aberrant reactivation of the AR despite ongoing androgen depletion. Recently, alternative splicing has been described as a mechanism giving rise to COOH-terminally truncated, constitutively active AR isoforms that can support the CRPCa phenotype. However, the pathologic origin of these truncated AR isoforms is unknown. The goal of this study was to investigate alterations in AR expression arising in a cell-based model of PCa progression driven by truncated AR isoform activity. We show that stable, high-level expression of truncated AR isoforms in 22Rv1 CRPCa cells is associated with intragenic rearrangement of an approximately 35-kb AR genomic segment harboring a cluster of previously described alternative AR exons. Analysis of genomic data from clinical specimens indicated that related AR intragenic copy number alterations occurred in CRPCa in the context of AR amplification. Cloning of the break fusion junction in 22Rv1 cells revealed long interspersed nuclear elements (LINE-1) flanking the rearranged segment and a DNA repair signature consistent with microhomology-mediated, break-induced replication. This rearrangement served as a marker for the emergence of a rare subpopulation of CRPCa cells expressing high levels of truncated AR isoforms during PCa progression in vitro. Together, these data provide the first report of AR intragenic rearrangements in CRPCa and an association with pathologic expression of truncated AR isoforms in a cell-based model of PCa progression.

AB - Androgen depletion for advanced prostate cancer (PCa) targets activity of the androgen receptor (AR), a steroid receptor transcription factor required for PCa growth. The emergence of lethal castration-resistant PCa (CRPCa) is marked by aberrant reactivation of the AR despite ongoing androgen depletion. Recently, alternative splicing has been described as a mechanism giving rise to COOH-terminally truncated, constitutively active AR isoforms that can support the CRPCa phenotype. However, the pathologic origin of these truncated AR isoforms is unknown. The goal of this study was to investigate alterations in AR expression arising in a cell-based model of PCa progression driven by truncated AR isoform activity. We show that stable, high-level expression of truncated AR isoforms in 22Rv1 CRPCa cells is associated with intragenic rearrangement of an approximately 35-kb AR genomic segment harboring a cluster of previously described alternative AR exons. Analysis of genomic data from clinical specimens indicated that related AR intragenic copy number alterations occurred in CRPCa in the context of AR amplification. Cloning of the break fusion junction in 22Rv1 cells revealed long interspersed nuclear elements (LINE-1) flanking the rearranged segment and a DNA repair signature consistent with microhomology-mediated, break-induced replication. This rearrangement served as a marker for the emergence of a rare subpopulation of CRPCa cells expressing high levels of truncated AR isoforms during PCa progression in vitro. Together, these data provide the first report of AR intragenic rearrangements in CRPCa and an association with pathologic expression of truncated AR isoforms in a cell-based model of PCa progression.

UR - http://www.scopus.com/inward/record.url?scp=79952772097&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79952772097&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-10-1998

DO - 10.1158/0008-5472.CAN-10-1998

M3 - Article

C2 - 21248069

AN - SCOPUS:79952772097

VL - 71

SP - 2108

EP - 2117

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 6

ER -