A genome‐scale screen reveals context‐dependent ovarian cancer sensitivity to miRNA overexpression |
| |
| Authors: | Benjamin B Shields Chad V Pecot Hua Gao Elizabeth McMillan Malia Potts Christa Nagel Scott Purinton Ying Wang Cristina Ivan Hyun Seok Kim Robert J Borkowski Shaheen Khan Cristian Rodriguez‐Aguayo Gabriel Lopez‐Berestein Jayanthi Lea Adi Gazdar Keith A Baggerly Anil K Sood Michael A White |
| |
| Institution: | 1. Departments of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA;2. Center for RNA interference and Non‐Coding RNA, MD Anderson Cancer Center, Houston, TX, USA;3. Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, USA;4. Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX, USA;5. Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea;6. Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA;7. Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA |
| |
| 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. |
| |
| Keywords: | cancer cancer genetics microRNA miRNA ovarian cancer |
|
|
