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ABSTRACT #50BASIC SCIENCESGRADUATE STUDENTPOSTER presentationIntegrative Genomic Analysis of miRNAs in Lung AdenocarcinomaVarune R Ramnarine 1 , Greg L Stewart, Katey SS Enfield, Stephen Lam, Wan Lam1British Columbia Cancer Research CentreBackground /objectivesLung cancer represents an enormous health burden, representing the most common cause of cancer deathworldwide, with a five-year survival of less than 15%. micro RNAs (miRNAs) have emerged as major players inlung cancer oncogenesis, displaying both oncogenic and tumor suppressive functions. DNA copy number (CN)amplification of oncogenes is a major molecular mechanism driving cancer, and like protein coding genes, CNalterations can influence miRNA expression levels. We hypothesize that DNA copy number gain modulates theexpression of miRNAs important to cancer cell growth, and that integrative analysis can identify these cancerdriving miRNAs.62MethodsGlobal gene dosage profiles for 46 lung adenocarcinoma and paired adjacent non-malignant tissues weregenerated by array comparative genomic hybridization. miRNA sequencing analysis was performed on this samepanel of tumours and matched non-malignant tissues using Illumina GAXII small RNA sequencing technologies.CN and expression were correlated for each miRNA (Spearman's correlation >0.3, p
POSTER presentationGRADUATE STUDENTBASIC SCIENCESABSTRACT #51EPI-002 accelerates ligand dissociation from androgen receptor by disruptingN-terminus to C-terminus interactionRick Ding 1 , Nasrin (Rina) Mawji 1 , Raymond Andersen 2 , and Marianne D Sadar 11Genome Sciences Centre, British Columbia Cancer Agency; 2 Department of Chemistry and Earth& Ocean Sciences, UBCBackground /objectivesConstitutively active splice variants of androgen receptor (AR) lacking the ligand-binding domain (LBD) arelinked to the development and progression of castration recurrent prostate cancer (CRPC). Recent studiessuggest a constitutively active splice variant, ARv567es, is capable of interacting with full-length AR (ARfl),stabilizing and enhancing its ligand dependent activities. EPI-001, an AR antagonist targeting the N-terminusdomain (NTD) prevents N-terminus to C-terminus (N/C) interaction of AR, which is essential for ARantiparallel dimer formation. The ligand-dependent N/C interactions slow the dissociation of ligand from theLBD. Here we examine the effect of EPI-002, a stereoisomer of EPI-001, on ARv567es complexed with fulllengthAR and test the hypothesis that EPI-002 will cause ligand to dissociate more quickly because it blocksN/C interaction.The aim of this study is twofold. First we will examine the effects of AR v567es on the dissociation rate from thefull-length receptor. Then we will examine the effect of EPI-002 on the ligand dissociation rate of AR fl with andwithout the presence of AR v567es .MethodsLigand dissociation rates were examined in live cells using a radiolabelled synthetic androgen, 3H-R1881. Liganddissociation assay was used to investigate the effect of ARv567es on the dissociation rate of 3H-R1881 fromwild-type full-length AR (wt AR fl ) transfected in Cos-1 cells. We also examined the effect of EPI-002 on thedissociation rate of 3H-R1881 from 1) endogenous AR fl in LNCaP cells with a point mutation (codon 868,Thr to Ala), 2) wt AR fl in Cos-1 cells and 3) mixture of wt AR fl and ARv567es at 50:50 ratios in Cos-1 cells.Expressed AR proteins were detected by Western blot analysis.ResultsAR v567es had no effect on the dissociation of ligand from LBD. EPI-002 increased the ligand dissociation ratefrom endogenous ARfl in LNCaP and wt ARfl by ~13% and 30%, respectively. 30% inhibitory effect wasobserved on mixture of ARfl and AR v567es at 50:50 ratios. Levels of AR protein achieved by transfection werewithin normal physiological levels when compared to levels of endogenous AR expression in LNCaP cells.ConclusionsConsistent and optimal levels of expression of full-length to variant AR can be achieved by transient transfection.EPI-002 quickens the dissociation of androgen from mutant full-length AR, wild-type full-length AR and themixture of wild-type full-length and variant AR by disrupting N/C interaction. Together these data begin toreveal the potential of EPI-002 for the treatment of CRPC in which most patients have numerous tumors, eachwith varying levels of expression of full-length and variant AR.Oral/Poster Presentations * 2012 63
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