title: An in-tumor genetic screen reveals that the BET bromodomain protein, BRD4, is a potential therapeutic target in ovarian carcinoma.
abstract: High-grade serous ovarian carcinoma (HGSOC) is the most common and aggressive form of epithelial ovarian cancer, for which few targeted therapies exist. To search for new therapeutic target proteins, we performed an in vivo shRNA screen using an established human HGSOC cell line growing either subcutaneously or intraperitoneally in immunocompromised mice. We identified genes previously implicated in ovarian cancer such as AURKA1, ERBB3, CDK2, and mTOR, as well as several novel candidates including BRD4, VRK1, and GALK2. We confirmed, using both genetic and pharmacologic approaches, that the activity of BRD4, an epigenetic transcription modulator, is necessary for proliferation/survival of both an established human ovarian cancer cell line (OVCAR8) and a subset of primary serous ovarian cancer cell strains (DFs). Among the DFs tested, the strains sensitive to BRD4 inhibition revealed elevated expression of either MYCN or c-MYC, with MYCN expression correlating closely with JQ1 sensitivity. Accordingly, primary human xenografts derived from high-MYCN or c-MYC strains exhibited sensitivity to BRD4 inhibition. These data suggest that BRD4 inhibition represents a new therapeutic approach for MYC-overexpressing HGSOCs.
authors.affiliation: Departments of Cancer Biology, Harvard Medical School, Boston, MA 02115; and.
authors.forename: Maria Giuseppina
authors.initials: MG
authors.lastname: Baratta
authors.affiliation: Harvard Medical School, Boston, MA 02115; and Medical Oncology, and Broad Institute of Harvard and MIT, Cambridge, MA 02142.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Schinzel
authors.affiliation: Harvard Medical School, Boston, MA 02115; and Medical Oncology, and Broad Institute of Harvard and MIT, Cambridge, MA 02142.
authors.forename: Yaara
authors.initials: Y
authors.lastname: Zwang
authors.affiliation: Departments of Cancer Biology, Harvard Medical School, Boston, MA 02115; and Broad Institute of Harvard and MIT, Cambridge, MA 02142.
authors.forename: Pratiti
authors.initials: P
authors.lastname: Bandopadhayay
authors.affiliation: Departments of Cancer Biology, Harvard Medical School, Boston, MA 02115; and.
authors.forename: Christian
authors.initials: C
authors.lastname: Bowman-Colin
authors.affiliation: Departments of Cancer Biology.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kutt
authors.affiliation: Departments of Cancer Biology.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Curtis
authors.affiliation: Departments of Cancer Biology.
authors.forename: Huiying
authors.initials: H
authors.lastname: Piao
authors.affiliation: Departments of Cancer Biology.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Wong
authors.affiliation: Harvard Medical School, Boston, MA 02115; and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115;
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.affiliation: Departments of Cancer Biology, Harvard Medical School, Boston, MA 02115; and Medical Oncology, and Broad Institute of Harvard and MIT, Cambridge, MA 02142.
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.affiliation: Departments of Cancer Biology, Harvard Medical School, Boston, MA 02115; and Medical Oncology, and Broad Institute of Harvard and MIT, Cambridge, MA 02142.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Harvard Medical School, Boston, MA 02115; and Medical Oncology, and.
authors.forename: Ronny
authors.initials: R
authors.lastname: Drapkin
authors.affiliation: Harvard Medical School, Boston, MA 02115; and Medical Oncology, and Broad Institute of Harvard and MIT, Cambridge, MA 02142.
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.affiliation: Harvard Medical School, Boston, MA 02115; and Medical Oncology, and.
authors.forename: Joyce F
authors.initials: JF
authors.lastname: Liu
authors.affiliation: Departments of Cancer Biology, Harvard Medical School, Boston, MA 02115; and david_livingston@dfci.harvard.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Livingston
mesh_terms: D000818:Animals; D000077216:Carcinoma, Ovarian Epithelial; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D056726:Genetic Association Studies; D005820:Genetic Testing; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000628:therapy*; D009687:Nuclear Proteins / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000628:therapy*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins
keywords: BRD4; MYCN; in vivo screen; ovarian cancer; targeted therapy