title: Aberrant Retinoblastoma (RB)-E2F Transcriptional Regulation Defines Molecular Phenotypes of Osteosarcoma.
abstract: We previously identified two distinct molecular subtypes of osteosarcoma through gene expression profiling. These subtypes are associated with distinct tumor behavior and clinical outcomes. Here, we describe mechanisms that give rise to these molecular subtypes. Using bioinformatic analyses, we identified a significant association between deregulation of the retinoblastoma (RB)-E2F pathway and the molecular subtype with worse clinical outcomes. Xenotransplantation models recapitulated the corresponding behavior for each osteosarcoma subtype; thus, we used cell lines to validate the role of the RB-E2F pathway in regulating the prognostic gene signature. Ectopic RB resets the patterns of E2F regulated gene expression in cells derived from tumors with worse clinical outcomes (molecular phenotype 2) to those comparable with those observed in cells derived from tumors with less aggressive outcomes (molecular phenotype 1), providing a functional association between RB-E2F dysfunction and altered gene expression in osteosarcoma. DNA methyltransferase and histone deacetylase inhibitors similarly reset the transcriptional state of the molecular phenotype 2 cells from a state associated with RB deficiency to one seen with RB sufficiency. Our data indicate that deregulation of RB-E2F pathway alters the epigenetic landscape and biological behavior of osteosarcoma.
authors.affiliation: Animal Cancer Care and Research Program; Departments of Veterinary Clinical Sciences; Masonic Cancer Center.
authors.forename: Milcah C
authors.initials: MC
authors.lastname: Scott
authors.affiliation: Animal Cancer Care and Research Program; Departments of Veterinary Clinical Sciences.
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Sarver
authors.affiliation: Animal Cancer Care and Research Program; Departments of Veterinary Clinical Sciences; Masonic Cancer Center.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Tomiyasu
authors.affiliation: Animal Cancer Care and Research Program; Masonic Cancer Center; Veterinary Population Medicine.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Cornax
authors.affiliation: Masonic Cancer Center; Department of Surgery, School of Medicine.
authors.forename: Jamie
authors.initials: J
authors.lastname: Van Etten
authors.affiliation: Animal Cancer Care and Research Program; Department of Surgery, School of Medicine; Veterinary Medicine Graduate Program, College of Veterinary Medicine.
authors.forename: Jyotika
authors.initials: J
authors.lastname: Varshney
authors.affiliation: Animal Cancer Care and Research Program; Masonic Cancer Center; Veterinary Population Medicine.
authors.forename: M Gerard
authors.initials: MG
authors.lastname: O'Sullivan
authors.affiliation: Animal Cancer Care and Research Program; Masonic Cancer Center; Department of Surgery, School of Medicine.
authors.forename: Subbaya
authors.initials: S
authors.lastname: Subramanian
authors.affiliation: Animal Cancer Care and Research Program; Departments of Veterinary Clinical Sciences; Masonic Cancer Center; Stem Cell Institute; Center for Immunology, University of Minnesota, Minneapolis, Minnesota 55455. Electronic address: stolson@uic.edu.
authors.forename: Jaime F
authors.initials: JF
authors.lastname: Modiano
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004285:Dogs; D050684:E2F Transcription Factors / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D012516:Osteosarcoma / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D016160:Retinoblastoma Protein / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: D050684:E2F Transcription Factors; D016160:Retinoblastoma Protein
keywords: E2F transcription factor; chromatin remodeling; gene expression; osteosarcoma; retinoblastoma protein (pRb, RB)