title: A genome-scale screen reveals context-dependent ovarian cancer sensitivity to miRNA overexpression.
abstract: Large-scale molecular annotation of epithelial ovarian cancer (EOC) indicates remarkable heterogeneity in the etiology of that disease. This diversity presents a significant obstacle against intervention target discovery. However, inactivation of miRNA biogenesis is commonly associated with advanced disease. Thus, restoration of miRNA activity may represent a common vulnerability among diverse EOC oncogenotypes. To test this, we employed genome-scale, gain-of-function, miRNA mimic toxicity screens in a large, diverse spectrum of EOC cell lines. We found that all cell lines responded to at least some miRNA mimics, but that the nature of the miRNA mimics provoking a response was highly selective within the panel. These selective toxicity profiles were leveraged to define modes of action and molecular response indicators for miRNA mimics with tumor-suppressive characteristics in vivo. A mechanistic principle emerging from this analysis was sensitivity of EOC to miRNA-mediated release of cell fate specification programs, loss of which may be a prerequisite for development of this disease.
authors.affiliation: Departments of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Shields
authors.affiliation: Center for RNA interference and Non-Coding RNA, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Chad V
authors.initials: CV
authors.lastname: Pecot
authors.affiliation: Departments of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Gao
authors.affiliation: Departments of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McMillan
authors.affiliation: Departments of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Malia
authors.initials: M
authors.lastname: Potts
authors.affiliation: Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Christa
authors.initials: C
authors.lastname: Nagel
authors.affiliation: Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Purinton
authors.affiliation: Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ivan
authors.affiliation: Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hyun Seok
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Departments of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Borkowski
authors.affiliation: Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Shaheen
authors.initials: S
authors.lastname: Khan
authors.affiliation: Center for RNA interference and Non-Coding RNA, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Cristian
authors.initials: C
authors.lastname: Rodriguez-Aguayo
authors.affiliation: Center for RNA interference and Non-Coding RNA, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.affiliation: Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Jayanthi
authors.initials: J
authors.lastname: Lea
authors.affiliation: Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Adi
authors.initials: A
authors.lastname: Gazdar
authors.affiliation: Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Baggerly
authors.affiliation: Center for RNA interference and Non-Coding RNA, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.affiliation: Departments of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA michael.white@utsouthwestern.edu.
authors.forename: Michael A
authors.initials: MA
authors.lastname: White
mesh_terms: D000818:Animals; D040761:Biomimetic Materials / Q000008:administration & dosage* / Q000494:pharmacology; D000077216:Carcinoma, Ovarian Epithelial; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055106:Genome-Wide Association Study; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D035683:MicroRNAs
keywords: cancer; cancer genetics; miRNA; microRNA; ovarian cancer