Journal of the National Cancer Institute Advance Access published online on May 27, 2008
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djn150
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© The Author 2008. Published by Oxford University Press.
ARTICLES |
Estrogen-Dependent Signaling in a Molecularly Distinct Subclass of Aggressive Prostate Cancer
Affiliations of authors: Department of Pathology (SRS, KDM, FD, SP, LAJ, JT, MAR) and Channing Laboratory (MJS), Brigham and Women's Hospital, Boston, MA; Harvard Medical School, Boston, MA (SRS, KDM, FD, SP, LAM, PWK, MJS, MAR); Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA (YH, TRG, MAR); The Dana-Farber Cancer Institute, Boston, MA (YH, ML, PWK, MB, TRG, MAR); Institute of Pathology, University Hospital of Ulm, Ulm, Germany (SP); Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT (AS); Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden (YP, HOA, SC, KF); Department of Urology, Örebro University Hospital, Örebro, Sweden (OA, SOA); Department of Epidemiology, Harvard School of Public Health, Boston, MA (HOA, LAM, MJS); Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy (SC); Department of Pathology, University of Michigan Medical School, Ann Arbor, MI (AMC, DR, ST); Department of Urology, University Hospital Linköping, Linköping, Sweden (EV)
Correspondence to: Mark A. Rubin, MD, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, 1300 York Ave, Rm C 410-A (or Box No. 69), New York, NY 10021 (e-mail: rubinma{at}med.cornell.edu).
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 ER
agonist treatment (ER 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 ER agonist treatment (ER 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.
| CONTEXT AND CAVEATS Prior knowledge An aggressive form of prostate cancer has been identified that expresses the transmembrane protease, serine 2—v-ets erythroblastosis virus E26 oncogene homolog (avian) (TMPRSS2–ERG) fusion gene. Study design Partitioning and classification models were used to determine the gene expression profile of the TMPRSS2–ERG fusion using samples from the Physicians’ Health Study and the Swedish Watchful Waiting cohorts. Computational functional analysis of the profile was performed to determine the molecular pathways involved in regulating TMPRSS2–ERG expression. Viability and TMPRSS2–ERG expression of an androgen receptor–negative prostate cancer cell line were assayed after treatment with vehicle or estrogenic compounds. Contributions
An 87-gene expression signature for TMPRSS2–ERG tumors was identified that was associated with estrogen receptor (ER) signaling pathways. In androgen receptor–negative prostate cancer cells, treatment with an ERβ agonist decreased cell viability and TMPRSS2–ERG expression but treatment with an ER Implications TMPRSS2–ERG fusion prostate cancers are molecularly distinct from other prostate cancers. TMPRSS2–ERG expression is regulated by estrogen receptor signaling pathways. Limitations The studies with estrogenic compounds were performed in vitro with cell lines, and thus, the specific effects of these compounds on TMPRSS2–ERG prostate cancer is still unknown.
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Manuscript received July 9, 2007; revised March 20, 2008; accepted April 9, 2008.
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