Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer.
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 ERbeta agonist (ERbeta 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 ERalpha agonist treatment (ERalpha 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 ERbeta agonist treatment (fold change over internal control, ERbeta 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 ERalpha agonist treatment (ERalpha 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.
Setlur
Sunita R
SR
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
Mertz
Kirsten D
KD
Hoshida
Yujin
Y
Demichelis
Francesca
F
Lupien
Mathieu
M
Perner
Sven
S
Sboner
Andrea
A
Pawitan
Yudi
Y
Andrén
Ove
O
Johnson
Laura A
LA
Tang
Jeff
J
Adami
Hans-Olov
HO
Calza
Stefano
S
Chinnaiyan
Arul M
AM
Rhodes
Daniel
D
Tomlins
Scott
S
Fall
Katja
K
Mucci
Lorelei A
LA
Kantoff
Philip W
PW
Stampfer
Meir J
MJ
Andersson
Swen-Olof
SO
Varenhorst
Eberhard
E
Johansson
Jan-Erik
JE
Brown
Myles
M
Golub
Todd R
TR
Rubin
Mark A
MA
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D019540:Area Under Curve; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D018076:DNA, Complementary / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006306:Health Surveys; D006801:Humans; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D010636:Phenols; D010820:Physicians / Q000706:statistics & numerical data; D016133:Polymerase Chain Reaction; D011422:Propionates / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013548:Sweden / Q000453:epidemiology; D014162:Transfection
C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D018931:Antineoplastic Agents, Hormonal; D018076:DNA, Complementary; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D009570:Nitriles; D015514:Oncogene Proteins, Fusion; D010636:Phenols; D011422:Propionates; D011720:Pyrazoles; C515553:TMPRSS2-ERG fusion protein, human; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol; D004958:Estradiol; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human