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

Setlur, Sunita R. (författare)
Mertz, Kirsten D. (författare)
Hoshida, Yujin (författare)
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Demichelis, Francesca (författare)
Lupien, Mathieu (författare)
Perner, Sven (författare)
Sboner, Andrea (författare)
Pawitan, Yudi (författare)
Andrén, Ove, (författare)
Örebro universitet, Hälsoakademin
Johnson, Laura A. (författare)
Tang, Jeff (författare)
Adami, Hans-Olov (författare)
Calza, Stefano (författare)
Chinnaiyan, Arul M. (författare)
Rhodes, Daniel (författare)
Tomlins, Scott (författare)
Fall, Katja (författare)
Mucci, Lorelei A. (författare)
Kantoff, Philip W. (författare)
Stampfer, Meir J. (författare)
Andersson, Swen-Olof, (författare)
Örebro universitet, Hälsoakademin
Varenhorst, Eberhard (författare)
Johansson, Jan-Erik, (författare)
Örebro universitet, Hälsoakademin
Brown, Myles (författare)
Golub, Todd R. (författare)
Rubin, Mark A. (författare)
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Ingår i: Journal of the National Cancer Institute. - Oxford : Oxford univ. press. - 0027-8874 .- 1460-2105. ; 100:11, s. 815-825
  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
  • <p>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 &lt; .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.</p>


MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Urologi och njurmedicin (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Urology and Nephrology (hsv//eng)


Antineoplastic Agents; Hormonal/*pharmacology/therapeutic use
Area Under Curve
Blotting; Western
Cell Line; Tumor
Cell Survival/drug effects
Chromatin Immunoprecipitation
DNA; Complementary/metabolism
Estrogen Receptor alpha/*antagonists & inhibitors/metabolism
Estrogen Receptor beta/*agonists/metabolism
Gene Expression Profiling
Gene Expression Regulation; Neoplastic/drug effects
Health Surveys
Neoplasms; Hormone-Dependent/drug therapy/*metabolism/pathology
Oncogene Proteins; Fusion/*metabolism
Physicians/statistics & numerical data
Polymerase Chain Reaction
Prostatic Neoplasms/drug therapy/*metabolism/pathology
Serine Endopeptidases/metabolism
Signal Transduction/drug effects
MEDICINE Surgery Oncology
MEDICIN Kirurgi Onkologi
MEDICINE Surgery Surgical research Urology and andrology
MEDICIN Kirurgi Kirurgisk forskning Urologi och andrologi

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