title: Proteomic-coupled-network analysis of T877A-androgen receptor interactomes can predict clinical prostate cancer outcomes between White (non-Hispanic) and African-American groups.
abstract: The androgen receptor (AR) remains an important contributor to the neoplastic evolution of prostate cancer (CaP). CaP progression is linked to several somatic AR mutational changes that endow upon the AR dramatic gain-of-function properties. One of the most common somatic mutations identified is Thr877-to-Ala (T877A), located in the ligand-binding domain, that results in a receptor capable of promiscuous binding and activation by a variety of steroid hormones and ligands including estrogens, progestins, glucocorticoids, and several anti-androgens. In an attempt to further define somatic mutated AR gain-of-function properties, as a consequence of its promiscuous ligand binding, we undertook a proteomic/network analysis approach to characterize the protein interactome of the mutant T877A-AR in LNCaP cells under eight different ligand-specific treatments (dihydrotestosterone, mibolerone, R1881, testosterone, estradiol, progesterone, dexamethasone, and cyproterone acetate). In extending the analysis of our multi-ligand complexes of the mutant T877A-AR we observed significant enrichment of specific complexes between normal and primary prostatic tumors, which were furthermore correlated with known clinical outcomes. Further analysis of certain mutant T877A-AR complexes showed specific population preferences distinguishing primary prostatic disease between white (non-Hispanic) vs. African-American males. Moreover, these cancer-related AR-protein complexes demonstrated predictive survival outcomes specific to CaP, and not for breast, lung, lymphoma or medulloblastoma cancers. Our study, by coupling data generated by our proteomics to network analysis of clinical samples, has helped to define real and novel biological pathways in complicated gain-of-function AR complex systems.
authors.affiliation: Biotechnology Research Institute - National Research Council, Montréal, QC, Canada.
authors.forename: Naif
authors.initials: N
authors.lastname: Zaman
authors.affiliation: Lady Davis Institute for Medical Research, Segal Cancer Centre - Jewish General Hospital, Montréal, QC, Canada.
authors.forename: Paresa N
authors.initials: PN
authors.lastname: Giannopoulos
authors.affiliation: Biotechnology Research Institute - National Research Council, Montréal, QC, Canada; Lady Davis Institute for Medical Research, Segal Cancer Centre - Jewish General Hospital, Montréal, QC, Canada.
authors.forename: Shafinaz
authors.initials: S
authors.lastname: Chowdhury
authors.affiliation: Institut de recherche en immunologie et en cancérologie, Université de Montréal, Montréal, QC, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Bonneil
authors.affiliation: Institut de recherche en immunologie et en cancérologie, Université de Montréal, Montréal, QC, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Thibault
authors.affiliation: Biotechnology Research Institute - National Research Council, Montréal, QC, Canada.
authors.forename: Edwin
authors.initials: E
authors.lastname: Wang
authors.affiliation: Lady Davis Institute for Medical Research, Segal Cancer Centre - Jewish General Hospital, Montréal, QC, Canada; Department of Medicine, Department of Oncology and Division of Experimental Medicine, McGill University, Montréal, QC, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Trifiro
authors.affiliation: Lady Davis Institute for Medical Research, Segal Cancer Centre - Jewish General Hospital, Montréal, QC, Canada; Department of Medicine, Department of Oncology and Division of Experimental Medicine, McGill University, Montréal, QC, Canada.
authors.forename: Miltiadis
authors.initials: M
authors.lastname: Paliouras
mesh_terms: D001741:Black or African American / Q000235:genetics*; D001665:Binding Sites; D045744:Cell Line, Tumor; D012739:Gonadal Steroid Hormones / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000208:ethnology* / Q000378:metabolism / Q000473:pathology; D017433:Protein Structure, Secondary; D040901:Proteomics; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D016019:Survival Analysis; D044465:White People / Q000208:ethnology / Q000235:genetics*
chemical_list: C410798:AR protein, human; D012739:Gonadal Steroid Hormones; D011944:Receptors, Androgen