Dynamic rewiring of the androgen receptor protein interaction network correlates with prostate cancer clinical outcomes

  1. Get@NRC: Dynamic rewiring of the androgen receptor protein interaction network correlates with prostate cancer clinical outcomes (Opens in a new window)
DOIResolve DOI: http://doi.org/10.1039/c1ib00038a
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Journal titleIntegrative Biology
Pages10201032; # of pages: 13
Subjectandrogen receptor; animal cell; article; carcinogenesis; comparative study; controlled study; correlation analysis; gene mutation; genetic variability; human; human tissue; malignant transformation; mass spectrometry; microarray analysis; nonhuman; outcomes research; priority journal; prognosis; prostate cancer; protein interaction; proteomics; systems biology; Animals; Cell Transformation, Neoplastic; Cercopithecus aethiops; Chromatography, Liquid; COS Cells; Disease Progression; Genetic Variation; Humans; Male; Polymorphism, Single Nucleotide; Prostatic Neoplasms; Protein Interaction Maps; Protein Isoforms; Proteomics; Receptors, Androgen; Systems Biology; Tandem Mass Spectrometry
AbstractThe androgen receptor (AR) is a ligand-inducible transcription factor, a member of the nuclear receptor superfamily, which plays an important role in the development and progression of prostate cancer (CaP). The transformation to CaP has been linked to several somatic AR gene mutations and changes in AR protein complex formation, which in turn increase the potential activity of the receptor. Thus, to address the mechanism of AR-mediated neoplastic transformation, we developed in vitro methodology to isolate and characterize, via mass spectrometry, AR complexes of three AR genetic variants: wild type-AR, and two somatic gain-of-function AR prostatic mutants (T877A-AR and 0CAG-AR isoforms). To fully characterize the significance of our large raw data set, we employed a sophisticated systems biology approach to create an integrative protein-interaction network profile for each AR isoform. Our comparative analysis identified subnetwork cluster profiles for AR isoforms (WT, T877A, and 0CAG) that segregated AR isoforms on the basis of androgen stimulation conditions and mutant aggressiveness. Furthermore, results from additional correlative gene microarray analysis studies of all three AR isoform (WT, T877A, 0CAG) subnetwork clusters were assessed and found to be significantly enriched in tumor versus normal prostate tissues. We also identified two AR-interaction clusters, containing 21 and 30 proteins, respectively, that showed unfavourable prognosis outcome of recurrent cancers, on the basis of PSA, Gleason score and combined PSA/Gleason score. In conclusion, we have characterized a large panel of novel AR-interacting proteins, through a combined proteomics/systems biology screen, that are of clinical relevance and could potentially serve as novel markers for diagnosis and prognosis of CaP. © 2011 The Royal Society of Chemistry.
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AffiliationNational Research Council Canada (NRC-CNRC); NRC Biotechnology Research Institute (BRI-IRB)
Peer reviewedYes
NPARC number21271285
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Record identifier23465d19-773c-4381-ad37-c8e40d73095a
Record created2014-03-24
Record modified2016-05-09
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