| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Liu, Joyce F. Wong, Laura C. Bradner, James E. Kutt, Jennifer Curtis, Jennifer Beroukhim, Rameen Livingston, David M. Zwang, Yaara Bandopadhayay, Pratiti Hahn, William C. Bowman-colin, Christian Piao, Huiying Kung, Andrew L. Schinzel, Anna C. Baratta, Maria Giuseppina Drapkin, Ronny |
| Description |
Author Affiliation: Baratta MG ( Departments of Cancer Biology, Harvard Medical School, Boston, MA 02115); Schinzel AC ( Harvard Medical School, Boston, MA 02115); Zwang Y ( Harvard Medical School, Boston, MA 02115); Bandopadhayay P ( Departments of Cancer Biology, Harvard Medical School, Boston, MA 02115); Bowman-Colin C ( Departments of Cancer Biology, Harvard Medical School, Boston, MA 02115); Kutt J ( Departments of Cancer Biology.); Curtis J ( Departments of Cancer Biology.); Piao H ( Departments of Cancer Biology.); Wong LC ( Departments of Cancer Biology.); Kung AL ( Harvard Medical School, Boston, MA 02115); Beroukhim R ( Departments of Cancer Biology, Harvard Medical School, Boston, MA 02115); Bradner JE ( Departments of Cancer Biology, Harvard Medical School, Boston, MA 02115); Drapkin R ( Harvard Medical School, Boston, MA 02115); Hahn WC ( Harvard Medical School, Boston, MA 02115); Liu JF ( Harvard Medical School, Boston, MA 02115); Livingston DM ( Departments of Cancer Biology, Harvard Medical School, Boston, MA 02115); |
| 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. |
| ISSN |
00278424 |
| e-ISSN |
10916490 |
| Journal |
Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number |
1 |
| Volume Number |
112 |
| Language |
English |
| Publisher |
National Academy of Sciences |
| Publisher Date |
2015-01-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Genetic Testing Molecular Targeted Therapy Neoplasms, Glandular And Epithelial Genetics Therapy Nuclear Proteins Metabolism Ovarian Neoplasms Transcription Factors Animals Cell Line, Tumor Cell Proliferation Genetic Association Studies Mice Proto-Oncogene Proteins C-myc RNA, Small Interfering Xenograft Model Antitumor Assays Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Multidisciplinary |
