Estrogen-Dependent Signaling in a Molecularly Distinct Subclass of Aggressive Prostate Cancer

• Published in: JNCI : Journal of the National Cancer Institute 2008-06, Vol.100 (11), p.815-825
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents, Hormonal - pharmacology; Antineoplastic Agents, Hormonal - therapeutic use; Area Under Curve; Biological and medical sciences; Blotting, Western; Cell Line, Tumor; Cell Survival - drug effects; Cellular biology; Chromatin Immunoprecipitation; DNA, Complementary - metabolism; Estradiol - pharmacology; Estrogen Receptor alpha - antagonists & inhibitors; Estrogen Receptor alpha - metabolism; Estrogen Receptor alpha/antagonists & inhibitors/metabolism; Estrogen Receptor beta - agonists; Estrogen Receptor beta - metabolism; Estrogen Receptor beta/agonists/metabolism; Estrogens - metabolism; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Health Surveys; Humans; Kirurgi; Kirurgisk forskning; Male; Medical sciences; MEDICIN; Medicin och hälsovetenskap; MEDICINE; Molecular biology; Neoplasms, Hormone-Dependent - drug therapy; Neoplasms, Hormone-Dependent - metabolism; Neoplasms, Hormone-Dependent - pathology; Nephrology. Urinary tract diseases; Nitriles - pharmacology; Oncogene Proteins, Fusion - metabolism; Oncology; Onkologi; Phenols; Physicians - statistics & numerical data; Polymerase Chain Reaction; Propionates - pharmacology; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Prostatic Neoplasms/drug therapy/metabolism/pathology; Pyrazoles - pharmacology; Serine Endopeptidases - metabolism; Signal transduction; Signal Transduction - drug effects; Surgery; Surgical research; Sweden - epidemiology; Transfection; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Urologi och andrologi; Urology and andrology
• ISSN: 0027-8874; 1460-2105; 1460-2105
• DOI: 10.1093/jnci/djn150

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.