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J Natl Cancer Inst DOI:10.1093/jnci/djn150

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

Publication TypeJournal Article
Year of Publication2008
AuthorsSetlur, SR, Mertz, KD, Hoshida, Y, Demichelis, F, Lupien, M, Perner, S, Sboner, A, Pawitan, Y, Andrén, O, Johnson, LA, Tang, J, Adami, H-O, Calza, S, Chinnaiyan, AM, Rhodes, D, Tomlins, S, Fall, K, Mucci, LA, Kantoff, PW, Stampfer, MJ, Andersson, S-O, Varenhorst, E, Johansson, J-E, Brown, M, Golub, TR, Rubin, MA
JournalJ Natl Cancer Inst
Date Published2008 Jun 04
KeywordsAntineoplastic Agents, Hormonal, Area Under Curve, Blotting, Western, Cell Line, Tumor, Cell Survival, Chromatin Immunoprecipitation, DNA, Complementary, Estradiol, Estrogen Receptor alpha, Estrogen Receptor beta, Estrogens, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Health Surveys, Humans, Male, Neoplasms, Hormone-Dependent, Nitriles, Oncogene Proteins, Fusion, Phenols, Physicians, Polymerase Chain Reaction, Propionates, Prostatic Neoplasms, Pyrazoles, Serine Endopeptidases, Signal Transduction, Sweden, Transfection

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

CONCLUSIONS: TMPRSS2-ERG fusion prostate cancer is a distinct molecular subclass. TMPRSS2-ERG expression is regulated by a novel ER-dependent mechanism.


Alternate JournalJ. Natl. Cancer Inst.
PubMed ID18505969
PubMed Central IDPMC3073404
Grant ListR01AG21404 / AG / NIA NIH HHS / United States
P50 CA090381 / CA / NCI NIH HHS / United States
R01 AG021404 / AG / NIA NIH HHS / United States
R01 AG021404-05 / AG / NIA NIH HHS / United States
P50 CA090381-10 / CA / NCI NIH HHS / United States