title: A Dexamethasone-regulated Gene Signature Is Prognostic for Poor Survival in Glioblastoma Patients.
abstract: BACKGROUND
  Dexamethasone is reported to induce both tumor-suppressive and tumor-promoting effects. The purpose of this study was to identify the genomic impact of dexamethasone in glioblastoma stem cell (GSC) lines and its prognostic value; furthermore, to identify drugs that can counter these side effects of dexamethasone exposure.
  
  
  METHODS
  We utilized 3 independent GSC lines with tumorigenic potential for this study. Whole-genome expression profiling and pathway analyses were done with dexamethasone-exposed and control cells. GSCs were also co-exposed to dexamethasone and temozolomide. Risk scores were calculated for most affected genes, and their associations with survival in The Cancer Genome Atlas and Repository of Molecular Brain Neoplasia Data databases. In silico Connectivity Map analysis identified camptothecin as antagonist to dexamethasone-induced negative effects.
  
  
  RESULTS
  Pathway analyses predicted an activation of dexamethasone network (z-score: 2.908). Top activated canonical pathways included "role of breast cancer 1 in DNA damage response" (P=1.07E-04). GSCs were protected against temozolomide-induced apoptosis when coincubated with dexamethasone. Altered cellular functions included cell movement, cell survival, and apoptosis with z-scores of 2.815, 5.137, and -3.122, respectively. CCAAT/enhancer binding protein beta (CEBPB) was activated in a dose dependent manner specifically in slow-dividing "stem-like" cells. CEBPB was activated in dexamethasone-treated orthotopic tumors. Patients with high risk scores had significantly shorter survival. Camptothecin was validated as potential partial neutralizer of dexamethasone-induced oncogenic effects.
  
  
  CONCLUSIONS
  Dexamethasone exposure induces a genetic program and CEBPB expression in GSCs that adversely affects key cellular functions and response to therapeutics. High risk scores associated with these genes have negative prognostic value in patients. Our findings further suggest camptothecin as a potential neutralizer of adverse dexamethasone-mediated effects.
authors.affiliation: *Department of Anesthesiology, Bern University Hospital Inselspital, Bern, Switzerland Departments of †Cancer Systems Imaging ‡Diagnostic Imaging §Neurosurgery and Brain Tumor Center ∥Radiation Oncology, Division of Radiation Oncology #Neurosurgery, Cancer Systems Imaging, and Cancer Biology **Cancer Systems Imaging, and Diagnostic Imaging, The University of Texas MD Anderson Cancer Center ¶Department of Neurosurgery, Baylor College of Medicine, Houston, TX.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Luedi
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Singh
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Mosley
authors.forename: Masumeh
authors.initials: M
authors.lastname: Hatami
authors.forename: Joy
authors.initials: J
authors.lastname: Gumin
authors.forename: Erik P
authors.initials: EP
authors.lastname: Sulman
authors.forename: Frederick F
authors.initials: FF
authors.lastname: Lang
authors.forename: Frank
authors.initials: F
authors.lastname: Stueber
authors.forename: Pascal O
authors.initials: PO
authors.lastname: Zinn
authors.forename: Rivka R
authors.initials: RR
authors.lastname: Colen
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000401:mortality*; D045744:Cell Line, Tumor; D002470:Cell Survival; D003907:Dexamethasone / Q000494:pharmacology*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005909:Glioblastoma / Q000401:mortality*; D006801:Humans; D051379:Mice; D011379:Prognosis; D013234:Stem Cells / Q000187:drug effects; D016019:Survival Analysis
chemical_list: D018931:Antineoplastic Agents, Hormonal; D003907:Dexamethasone