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Please use this identifier to cite or link to this item: http://hdl.handle.net/2262/53769

Title: Endothelial NOS, estrogen receptor beta, and HIFs cooperate in the activation of a prognostic transcriptional pattern in aggressive human prostate cancer.
Author: FINN, STEPHEN
Sponsor: 
Name Grant Number
5R01CA131945
5P50CA90381

Author's Homepage: http://people.tcd.ie/finns
Keywords: Oncology
Prostate cancer
Issue Date: 2009
Publisher: American Society for Clinical Investigation
Citation: Nanni S, Benvenuti V, Grasselli A, Priolo C, Aiello A, Mattiussi S, Colussi C, Lirangi V, Illi B, D'Eletto M, Cianciulli AM, Gallucci M, De Carli P, Sentinelli S, Mottolese M, Carlini P, Strigari L, Finn S, Mueller E, Arcangeli G, Gaetano C, Capogrossi MC, Donnorso RP, Bacchetti S, Sacchi A, Pontecorvi A, Loda M, Farsetti A, Endothelial NOS, estrogen receptor beta, and HIFs cooperate in the activation of a prognostic transcriptional pattern in aggressive human prostate cancer., The Journal of clinical investigation, 119, 5, 2009, 1093-108
Series/Report no.: The Journal of clinical investigation;
119;
5;
Abstract: The identification of biomarkers that distinguish between aggressive and indolent forms of prostate cancer (PCa) is crucial for diagnosis and treatment. In this study, we used cultured cells derived from prostate tissue from patients with PCa to define a molecular mechanism underlying the most aggressive form of PCa that involves the functional activation of eNOS and HIFs in association with estrogen receptor β (ERβ). Cells from patients with poor prognosis exhibited a constitutively hypoxic phenotype and increased NO production. Upon estrogen treatment, formation of ERβ/eNOS, ERβ/HIF-1α, or ERβ/HIF-2α combinatorial complexes led to chromatin remodeling and transcriptional induction of prognostic genes. Tissue microarray analysis, using an independent cohort of patients, established a hierarchical predictive power for these proteins, with expression of eNOS plus ERβ and nuclear eNOS plus HIF-2α being the most relevant indicators of adverse clinical outcome. Genetic or pharmacologic modulation of eNOS expression and activity resulted in reciprocal conversion of the transcriptional signature in cells from patients with bad or good outcome, respectively, highlighting the relevance of eNOS in PCa progression. Our work has considerable clinical relevance, since it may enable the earlier diagnosis of aggressive PCa through routine biopsy assessment of eNOS, ERβ, and HIF-2α expression. Furthermore, proposing eNOS as a therapeutic target fosters innovative therapies for PCa with NO inhibitors, which are employed in preclinical trials in non-oncological diseases.
Description: PUBLISHED
URI: http://hdl.handle.net/2262/53769
Related links: http://dx.crossref.org/10.1172%2FJCI35079
Appears in Collections:Histopathology & Morbid Anatomy (Scholarly Publications)

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