TY - JOUR
T1 - A genome-scale screen reveals context-dependent ovarian cancer sensitivity to miRNA overexpression
AU - Shields, Benjamin B.
AU - Pecot, Chad V.
AU - Gao, Hua
AU - McMillan, Elizabeth
AU - Potts, Malia
AU - Nagel, Christa
AU - Purinton, Scott
AU - Wang, Ying
AU - Ivan, Cristina
AU - Kim, Hyun Seok
AU - Borkowski, Robert J.
AU - Khan, Shaheen
AU - Rodriguez-Aguayo, Cristian
AU - Lopez-Berestein, Gabriel
AU - Lea, Jayanthi
AU - Gazdar, Adi
AU - Baggerly, Keith A.
AU - Sood, Anil K.
AU - White, Michael A.
N1 - Publisher Copyright:
© 2015 The Authors. Published under the terms of the CC BY 4.0 license.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - 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.
AB - 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.
KW - cancer
KW - cancer genetics
KW - miRNA
KW - microRNA
KW - ovarian cancer
UR - http://www.scopus.com/inward/record.url?scp=84955463400&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84955463400&partnerID=8YFLogxK
U2 - 10.15252/msb.20156308
DO - 10.15252/msb.20156308
M3 - Article
C2 - 26655797
AN - SCOPUS:84955463400
SN - 1744-4292
VL - 11
SP - 1
EP - 17
JO - Molecular Systems Biology
JF - Molecular Systems Biology
IS - 12
ER -