Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer

Sunita R. Setlur, Kirsten D. Mertz, Yujin Hoshida, Francesca Demichelis, Mathieu Lupien, Sven Perner, Andrea Sboner, Yudi Pawitan, Ove Andrén, Laura A. Johnson, Jeff Tang, Hans Olov Adami, Stefano Calza, Arul M. Chinnaiyan, Daniel Rhodes, Scott Tomlins, Katja Fall, Lorelei A. Mucci, Philip W. Kantoff, Meir J. StampferSwen Olof Andersson, Eberhard Varenhorst, Jan Erik Johansson, Myles Brown, Todd R. Golub, Mark A. Rubin

Research output: Contribution to journalArticle

231 Citations (Scopus)

Abstract

Background: The majority of prostate cancers harbor gene fusions of the 5′-untranslated region of the androgen-regulated transmembrane protease serine 2 (TMPRSS2) promoter with erythroblast transformation-specific transcription factor family members. The common fusion between TMPRESS2 and v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) is associated with a more aggressive clinical phenotype, implying the existence of a distinct subclass of prostate cancer defined by this fusion. Methods: We used complementary DNA-mediated annealing, selection, ligation, and extension to determine the expression profiles of 6144 transcriptionally informative genes in archived biopsy samples from 455 prostate cancer patients in the Swedish Watchful Waiting cohort (1987-1999) and the United States-based Physicians' Health Study cohort (1983-2003). A gene expression signature for prostate cancers with the TMPRSS2-ERG fusion was determined using partitioning and classification models and used in computational functional analysis. Cell proliferation and TMPRSS2-ERG expression in androgen receptor-negative (NCI-H660) prostate cancer cells after treatment with vehicle or estrogenic compounds were assessed by viability assays and quantitative polymerase chain reaction, respectively. All statistical tests were two-sided. Results: We identified an 87-gene expression signature that distinguishes TMPRSS2-ERG fusion prostate cancer as a discrete molecular entity (area under the curve = 0.80, 95% confidence interval [CI] = 0.792 to 0.81; P <. 001). Computational analysis suggested that this fusion signature was associated with estrogen receptor (ER) signaling. Viability of NCI-H660 cells decreased after treatment with estrogen (viability normalized to day 0, estrogen vs vehicle at day 8, mean = 2.04 vs 3.40, difference = 1.36, 95% CI = 1.12 to 1.62) or ERβ agonist (ERβ agonist vs vehicle at day 8, mean = 1.86 vs 3.40, difference = 1.54, 95% CI = 1.39 to 1.69) but increased after ERα agonist treatment (ERα agonist vs vehicle at day 8, mean = 4.36 vs 3.40, difference = 0.96, 95% CI = 0.68 to 1.23). Similarly, expression of TMPRSS2-ERG decreased after ERβ agonist treatment (fold change over internal control, ERβ agonist vs vehicle at 24 hours, NCI-H660, mean = 0.57- vs 1.0-fold, difference = 0.43-fold, 95% CI = 0.29- to 0.57-fold) and increased after ERα agonist treatment (ERα agonist vs vehicle at 24 hours, mean = 5.63- vs 1.0-fold, difference = 4.63-fold, 95% CI = 4.34- to 4.92-fold). Conclusions: TMPRSS2-ERG fusion prostate cancer is a distinct molecular subclass. TMPRSS2-ERG expression is regulated by a novel ER-dependent mechanism.

Original languageEnglish (US)
Pages (from-to)815-825
Number of pages11
JournalJournal of the National Cancer Institute
Volume100
Issue number11
DOIs
StatePublished - Jun 1 2008
Externally publishedYes

Fingerprint

Prostatic Neoplasms
Estrogens
Serine Proteases
Confidence Intervals
Transcriptome
Estrogen Receptors
Watchful Waiting
Erythroblasts
5' Untranslated Regions
Neoplasm Genes
Gene Fusion
Androgen Receptors
Therapeutics
Oncogenes
Androgens
Area Under Curve
Ligation
Cohort Studies
Transcription Factors
Complementary DNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer. / Setlur, Sunita R.; Mertz, Kirsten D.; Hoshida, Yujin; Demichelis, Francesca; Lupien, Mathieu; Perner, Sven; Sboner, Andrea; Pawitan, Yudi; Andrén, Ove; Johnson, Laura A.; Tang, Jeff; Adami, Hans Olov; Calza, Stefano; Chinnaiyan, Arul M.; Rhodes, Daniel; Tomlins, Scott; Fall, Katja; Mucci, Lorelei A.; Kantoff, Philip W.; Stampfer, Meir J.; Andersson, Swen Olof; Varenhorst, Eberhard; Johansson, Jan Erik; Brown, Myles; Golub, Todd R.; Rubin, Mark A.

In: Journal of the National Cancer Institute, Vol. 100, No. 11, 01.06.2008, p. 815-825.

Research output: Contribution to journalArticle

Setlur, SR, Mertz, KD, Hoshida, Y, Demichelis, F, Lupien, M, Perner, S, Sboner, A, Pawitan, Y, Andrén, O, Johnson, LA, Tang, J, Adami, HO, Calza, S, Chinnaiyan, AM, Rhodes, D, Tomlins, S, Fall, K, Mucci, LA, Kantoff, PW, Stampfer, MJ, Andersson, SO, Varenhorst, E, Johansson, JE, Brown, M, Golub, TR & Rubin, MA 2008, 'Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer', Journal of the National Cancer Institute, vol. 100, no. 11, pp. 815-825. https://doi.org/10.1093/jnci/djn150
Setlur, Sunita R. ; Mertz, Kirsten D. ; Hoshida, Yujin ; Demichelis, Francesca ; Lupien, Mathieu ; Perner, Sven ; Sboner, Andrea ; Pawitan, Yudi ; Andrén, Ove ; Johnson, Laura A. ; Tang, Jeff ; Adami, Hans Olov ; Calza, Stefano ; Chinnaiyan, Arul M. ; Rhodes, Daniel ; Tomlins, Scott ; Fall, Katja ; Mucci, Lorelei A. ; Kantoff, Philip W. ; Stampfer, Meir J. ; Andersson, Swen Olof ; Varenhorst, Eberhard ; Johansson, Jan Erik ; Brown, Myles ; Golub, Todd R. ; Rubin, Mark A. / Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer. In: Journal of the National Cancer Institute. 2008 ; Vol. 100, No. 11. pp. 815-825.
@article{218144b9052a4f2bb1fa32f782f0dc8a,
title = "Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer",
abstract = "Background: The majority of prostate cancers harbor gene fusions of the 5′-untranslated region of the androgen-regulated transmembrane protease serine 2 (TMPRSS2) promoter with erythroblast transformation-specific transcription factor family members. The common fusion between TMPRESS2 and v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) is associated with a more aggressive clinical phenotype, implying the existence of a distinct subclass of prostate cancer defined by this fusion. Methods: We used complementary DNA-mediated annealing, selection, ligation, and extension to determine the expression profiles of 6144 transcriptionally informative genes in archived biopsy samples from 455 prostate cancer patients in the Swedish Watchful Waiting cohort (1987-1999) and the United States-based Physicians' Health Study cohort (1983-2003). A gene expression signature for prostate cancers with the TMPRSS2-ERG fusion was determined using partitioning and classification models and used in computational functional analysis. Cell proliferation and TMPRSS2-ERG expression in androgen receptor-negative (NCI-H660) prostate cancer cells after treatment with vehicle or estrogenic compounds were assessed by viability assays and quantitative polymerase chain reaction, respectively. All statistical tests were two-sided. Results: We identified an 87-gene expression signature that distinguishes TMPRSS2-ERG fusion prostate cancer as a discrete molecular entity (area under the curve = 0.80, 95{\%} confidence interval [CI] = 0.792 to 0.81; P <. 001). Computational analysis suggested that this fusion signature was associated with estrogen receptor (ER) signaling. Viability of NCI-H660 cells decreased after treatment with estrogen (viability normalized to day 0, estrogen vs vehicle at day 8, mean = 2.04 vs 3.40, difference = 1.36, 95{\%} CI = 1.12 to 1.62) or ERβ agonist (ERβ agonist vs vehicle at day 8, mean = 1.86 vs 3.40, difference = 1.54, 95{\%} CI = 1.39 to 1.69) but increased after ERα agonist treatment (ERα agonist vs vehicle at day 8, mean = 4.36 vs 3.40, difference = 0.96, 95{\%} CI = 0.68 to 1.23). Similarly, expression of TMPRSS2-ERG decreased after ERβ agonist treatment (fold change over internal control, ERβ agonist vs vehicle at 24 hours, NCI-H660, mean = 0.57- vs 1.0-fold, difference = 0.43-fold, 95{\%} CI = 0.29- to 0.57-fold) and increased after ERα agonist treatment (ERα agonist vs vehicle at 24 hours, mean = 5.63- vs 1.0-fold, difference = 4.63-fold, 95{\%} CI = 4.34- to 4.92-fold). Conclusions: TMPRSS2-ERG fusion prostate cancer is a distinct molecular subclass. TMPRSS2-ERG expression is regulated by a novel ER-dependent mechanism.",
author = "Setlur, {Sunita R.} and Mertz, {Kirsten D.} and Yujin Hoshida and Francesca Demichelis and Mathieu Lupien and Sven Perner and Andrea Sboner and Yudi Pawitan and Ove Andr{\'e}n and Johnson, {Laura A.} and Jeff Tang and Adami, {Hans Olov} and Stefano Calza and Chinnaiyan, {Arul M.} and Daniel Rhodes and Scott Tomlins and Katja Fall and Mucci, {Lorelei A.} and Kantoff, {Philip W.} and Stampfer, {Meir J.} and Andersson, {Swen Olof} and Eberhard Varenhorst and Johansson, {Jan Erik} and Myles Brown and Golub, {Todd R.} and Rubin, {Mark A.}",
year = "2008",
month = "6",
day = "1",
doi = "10.1093/jnci/djn150",
language = "English (US)",
volume = "100",
pages = "815--825",
journal = "Journal of the National Cancer Institute",
issn = "0027-8874",
publisher = "Oxford University Press",
number = "11",

}

TY - JOUR

T1 - Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer

AU - Setlur, Sunita R.

AU - Mertz, Kirsten D.

AU - Hoshida, Yujin

AU - Demichelis, Francesca

AU - Lupien, Mathieu

AU - Perner, Sven

AU - Sboner, Andrea

AU - Pawitan, Yudi

AU - Andrén, Ove

AU - Johnson, Laura A.

AU - Tang, Jeff

AU - Adami, Hans Olov

AU - Calza, Stefano

AU - Chinnaiyan, Arul M.

AU - Rhodes, Daniel

AU - Tomlins, Scott

AU - Fall, Katja

AU - Mucci, Lorelei A.

AU - Kantoff, Philip W.

AU - Stampfer, Meir J.

AU - Andersson, Swen Olof

AU - Varenhorst, Eberhard

AU - Johansson, Jan Erik

AU - Brown, Myles

AU - Golub, Todd R.

AU - Rubin, Mark A.

PY - 2008/6/1

Y1 - 2008/6/1

N2 - Background: The majority of prostate cancers harbor gene fusions of the 5′-untranslated region of the androgen-regulated transmembrane protease serine 2 (TMPRSS2) promoter with erythroblast transformation-specific transcription factor family members. The common fusion between TMPRESS2 and v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) is associated with a more aggressive clinical phenotype, implying the existence of a distinct subclass of prostate cancer defined by this fusion. Methods: We used complementary DNA-mediated annealing, selection, ligation, and extension to determine the expression profiles of 6144 transcriptionally informative genes in archived biopsy samples from 455 prostate cancer patients in the Swedish Watchful Waiting cohort (1987-1999) and the United States-based Physicians' Health Study cohort (1983-2003). A gene expression signature for prostate cancers with the TMPRSS2-ERG fusion was determined using partitioning and classification models and used in computational functional analysis. Cell proliferation and TMPRSS2-ERG expression in androgen receptor-negative (NCI-H660) prostate cancer cells after treatment with vehicle or estrogenic compounds were assessed by viability assays and quantitative polymerase chain reaction, respectively. All statistical tests were two-sided. Results: We identified an 87-gene expression signature that distinguishes TMPRSS2-ERG fusion prostate cancer as a discrete molecular entity (area under the curve = 0.80, 95% confidence interval [CI] = 0.792 to 0.81; P <. 001). Computational analysis suggested that this fusion signature was associated with estrogen receptor (ER) signaling. Viability of NCI-H660 cells decreased after treatment with estrogen (viability normalized to day 0, estrogen vs vehicle at day 8, mean = 2.04 vs 3.40, difference = 1.36, 95% CI = 1.12 to 1.62) or ERβ agonist (ERβ agonist vs vehicle at day 8, mean = 1.86 vs 3.40, difference = 1.54, 95% CI = 1.39 to 1.69) but increased after ERα agonist treatment (ERα agonist vs vehicle at day 8, mean = 4.36 vs 3.40, difference = 0.96, 95% CI = 0.68 to 1.23). Similarly, expression of TMPRSS2-ERG decreased after ERβ agonist treatment (fold change over internal control, ERβ agonist vs vehicle at 24 hours, NCI-H660, mean = 0.57- vs 1.0-fold, difference = 0.43-fold, 95% CI = 0.29- to 0.57-fold) and increased after ERα agonist treatment (ERα agonist vs vehicle at 24 hours, mean = 5.63- vs 1.0-fold, difference = 4.63-fold, 95% CI = 4.34- to 4.92-fold). Conclusions: TMPRSS2-ERG fusion prostate cancer is a distinct molecular subclass. TMPRSS2-ERG expression is regulated by a novel ER-dependent mechanism.

AB - Background: The majority of prostate cancers harbor gene fusions of the 5′-untranslated region of the androgen-regulated transmembrane protease serine 2 (TMPRSS2) promoter with erythroblast transformation-specific transcription factor family members. The common fusion between TMPRESS2 and v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) is associated with a more aggressive clinical phenotype, implying the existence of a distinct subclass of prostate cancer defined by this fusion. Methods: We used complementary DNA-mediated annealing, selection, ligation, and extension to determine the expression profiles of 6144 transcriptionally informative genes in archived biopsy samples from 455 prostate cancer patients in the Swedish Watchful Waiting cohort (1987-1999) and the United States-based Physicians' Health Study cohort (1983-2003). A gene expression signature for prostate cancers with the TMPRSS2-ERG fusion was determined using partitioning and classification models and used in computational functional analysis. Cell proliferation and TMPRSS2-ERG expression in androgen receptor-negative (NCI-H660) prostate cancer cells after treatment with vehicle or estrogenic compounds were assessed by viability assays and quantitative polymerase chain reaction, respectively. All statistical tests were two-sided. Results: We identified an 87-gene expression signature that distinguishes TMPRSS2-ERG fusion prostate cancer as a discrete molecular entity (area under the curve = 0.80, 95% confidence interval [CI] = 0.792 to 0.81; P <. 001). Computational analysis suggested that this fusion signature was associated with estrogen receptor (ER) signaling. Viability of NCI-H660 cells decreased after treatment with estrogen (viability normalized to day 0, estrogen vs vehicle at day 8, mean = 2.04 vs 3.40, difference = 1.36, 95% CI = 1.12 to 1.62) or ERβ agonist (ERβ agonist vs vehicle at day 8, mean = 1.86 vs 3.40, difference = 1.54, 95% CI = 1.39 to 1.69) but increased after ERα agonist treatment (ERα agonist vs vehicle at day 8, mean = 4.36 vs 3.40, difference = 0.96, 95% CI = 0.68 to 1.23). Similarly, expression of TMPRSS2-ERG decreased after ERβ agonist treatment (fold change over internal control, ERβ agonist vs vehicle at 24 hours, NCI-H660, mean = 0.57- vs 1.0-fold, difference = 0.43-fold, 95% CI = 0.29- to 0.57-fold) and increased after ERα agonist treatment (ERα agonist vs vehicle at 24 hours, mean = 5.63- vs 1.0-fold, difference = 4.63-fold, 95% CI = 4.34- to 4.92-fold). Conclusions: TMPRSS2-ERG fusion prostate cancer is a distinct molecular subclass. TMPRSS2-ERG expression is regulated by a novel ER-dependent mechanism.

UR - http://www.scopus.com/inward/record.url?scp=44949204525&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=44949204525&partnerID=8YFLogxK

U2 - 10.1093/jnci/djn150

DO - 10.1093/jnci/djn150

M3 - Article

C2 - 18505969

AN - SCOPUS:44949204525

VL - 100

SP - 815

EP - 825

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

SN - 0027-8874

IS - 11

ER -