title: Expression of DRD2 Is Increased in Human Pancreatic Ductal Adenocarcinoma and Inhibitors Slow Tumor Growth in Mice.
abstract: Incidence of and mortality from pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, are almost equivalent, so better treatments are needed. We studied gene expression profiles of PDACs and the functions of genes with altered expression to identify new therapeutic targets.
  
  
  
  We performed microarray analysis to analyze gene expression profiles of 195 PDAC and 41 non-tumor pancreatic tissue samples. We undertook an extensive analysis of the PDAC transcriptome by superimposing interaction networks of proteins encoded by aberrantly expressed genes over signaling pathways associated with PDAC development to identify factors that might alter regulation of these pathways during tumor progression. We performed tissue microarray analysis to verify changes in expression of candidate protein using an independent set of 152 samples (40 nontumor pancreatic tissues, 63 PDAC sections, and 49 chronic pancreatitis samples). We validated the functional relevance of the candidate molecule using RNA interference or pharmacologic inhibitors in pancreatic cancer cell lines and analyses of xenograft tumors in mice.
  
  
  
  In an analysis of 38,276 human genes and loci, we identified 1676 genes that were significantly up-regulated and 1166 genes that were significantly down-regulated in PDAC compared with nontumor pancreatic tissues. One gene that was up-regulated and associated with multiple signaling pathways that are dysregulated in PDAC was G protein subunit αi2, which has not been previously associated with PDAC. G protein subunit αi2 mediates the effects of dopamine receptor D2 (DRD2) on cyclic adenosine monophosphate signaling; PDAC tissues had a slight but significant increase in DRD2 messenger RNA. Levels of DRD2 protein were substantially increased in PDACs, compared with non-tumor tissues, in tissue microarray analyses. RNA interference knockdown of DRD2 or inhibition with pharmacologic antagonists (pimozide and haloperidol) reduced proliferation of pancreatic cancer cells, induced endoplasmic reticulum stress and apoptosis, and reduced cell migration. RNA interference knockdown of DRD2 in pancreatic tumor cells reduced growth of xenograft tumors in mice, and administration of the DRD2 inhibitor haloperidol to mice with orthotopic xenograft tumors reduced final tumor size and metastasis.
  
  
  
  In gene expression profile analysis of PDAC samples, we found the DRD2 signaling pathway to be activated. Inhibition of DRD2 in pancreatic cancer cells reduced proliferation and migration, and slowed growth of xenograft tumors in mice. DRD2 antagonists routinely used for management of schizophrenia might be tested in patients with pancreatic cancer.
authors: Functional Genome Analysis, Deutsches Krebsforschungszentrum, Heidelberg, Germany; Department of Human Genetics, McGill University, Montreal, Quebec, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors: Pouria
authors: P
authors: Jandaghi
authors: Department of Human Genetics, McGill University, Montreal, Quebec, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors: Hamed S
authors: HS
authors: Najafabadi
authors: Functional Genome Analysis, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
authors: Andrea S
authors: AS
authors: Bauer
authors: Department of Biochemistry, McGill University, Montreal, Quebec, Canada; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
authors: Andreas I
authors: AI
authors: Papadakis
authors: ARC-NET Center for Applied Research on Cancer, University and Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors: Matteo
authors: M
authors: Fassan
authors: Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
authors: Anita
authors: A
authors: Hall
authors: Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
authors: Anie
authors: A
authors: Monast
authors: Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors: Magnus
authors: M
authors: von Knebel Doeberitz
authors: National Institute for Health Research, Liverpool Pancreas Biomedical Research Unit, Liverpool, UK.
authors: John P
authors: JP
authors: Neoptolemos
authors: National Institute for Health Research, Liverpool Pancreas Biomedical Research Unit, Liverpool, UK.
authors: Eithne
authors: E
authors: Costello
authors: National Institute for Health Research, Liverpool Pancreas Biomedical Research Unit, Liverpool, UK.
authors: William
authors: W
authors: Greenhalf
authors: ARC-NET Center for Applied Research on Cancer, University and Azienda Ospedaliera Universitaria Integrata, Verona, Italy; Department of Pathology and Diagnostics, Università di Verona, Verona, Italy.
authors: Aldo
authors: A
authors: Scarpa
authors: Institute for Pathology and Neuropathology, Universitätsklinikum Tübingen, Tübingen, Germany.
authors: Bence
authors: B
authors: Sipos
authors: Department of Human Genetics, McGill University, Montreal, Quebec, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors: Daniel
authors: D
authors: Auld
authors: Department of Human Genetics, McGill University, Montreal, Quebec, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors: Mark
authors: M
authors: Lathrop
authors: Department of Biochemistry, McGill University, Montreal, Quebec, Canada; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; Department of Pathology, McGill University, Montréal, Quebec, Canada; Department of Oncology, McGill University, Montréal, Quebec, Canada.
authors: Morag
authors: M
authors: Park
authors: Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors: Markus W
authors: MW
authors: Büchler
authors: Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors: Oliver
authors: O
authors: Strobel
authors: Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors: Thilo
authors: T
authors: Hackert
authors: Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors: Nathalia A
authors: NA
authors: Giese
authors: Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
authors: George
authors: G
authors: Zogopoulos
authors: Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; Department of Oncology, McGill University, Montréal, Quebec, Canada.
authors: Veena
authors: V
authors: Sangwan
authors: Department of Biochemistry, McGill University, Montreal, Quebec, Canada; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
authors: Sidong
authors: S
authors: Huang
authors: Department of Human Genetics, McGill University, Montreal, Quebec, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. Electronic address: Yasser.riazalhosseini@mcgill.ca.
authors: Yasser
authors: Y
authors: Riazalhosseini
authors: Functional Genome Analysis, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
authors: Jörg D
authors: JD
authors: Hoheisel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism* / Q000556:secondary; D016022:Case-Control Studies; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000235:genetics; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D055785:Gene Knockdown Techniques; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D010868:Pimozide / Q000494:pharmacology; D034741:RNA, Small Interfering; D017448:Receptors, Dopamine D2 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome; D056811:Unfolded Protein Response / Q000187:drug effects; D015854:Up-Regulation; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D065127:Dopamine D2 Receptor Antagonists; D006220:Haloperidol; D010868:Pimozide; D034741:RNA, Small Interfering; D017448:Receptors, Dopamine D2; D019892:eIF-2 Kinase; C581293:DRD2 protein, human; C000600618:DRD2 protein, mouse
keywords: Drug Repositioning; Pancreas; TMA; Unfolded Protein Response