Genome-wide gain-of-function screen for genes that induce epithelial-to-mesenchymal transition in breast cancer
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Dubravka Škalamera1,9, Mareike Dahmer-Heath1,9, Alexander J. Stevenson1,9, Cletus Pinto2, Esha T. Shah3,4, Sheena M. Daignault1, Nur Akmarina B.M. Said5,6, Melissa Davis7, Nikolas K. Haass1, Elizabeth D. Williams3,4,5, Brett G. Hollier3,4, Erik W. Thompson2,4, Brian Gabrielli1,9 and Thomas J. Gonda1,8
1 University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, QLD, Australia
2 St Vincent’s Institute of Medical Research and University of Melbourne Department of Surgery, St. Vincent’s Hospital, Melbourne, VIC, Australia
3 Australian Prostate Cancer Research Centre-Queensland, Brisbane, QLD, Australia
4 Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology,Translational Research Institute, Brisbane, QLD, Australia
5 Monash Institute of Medical Research (now Hudson Institute of Medical Research), Monash University, Melbourne, VIC, Australia
6 University of Malaya, Kuala Lumpur, Malaysia
7 The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
8 School of Pharmacy, University of Queensland, Brisbane, QLD, Australia
9 Mater Medical Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Australia
Dubravka Škalamera, email:
Thomas J. Gonda, email:
Keywords: high-content-screening, epithelial-mesenchymal transition, vimentin, lentiviral vectors, breast cancer
Received: March 08, 2016 Accepted: July 27, 2016 Published: August 16, 2016
Epithelial to mesenchymal transition (EMT) is a developmental program that has been implicated in progression, metastasis and therapeutic resistance of some carcinomas. To identify genes whose overexpression drives EMT, we screened a lentiviral expression library of 17000 human open reading frames (ORFs) using high-content imaging to quantitate cytoplasmic vimentin. Hits capable of increasing vimentin in the mammary carcinoma-derived cell line MDA-MB-468 were confirmed in the non-tumorigenic breast-epithelial cell line MCF10A. When overexpressed in this model, they increased the rate of cell invasion through Matrigel™, induced mesenchymal marker expression and reduced expression of the epithelial marker E-cadherin. In gene-expression datasets derived from breast cancer patients, the expression of several novel genes correlated with expression of known EMT marker genes, indicating their in vivo relevance. As EMT-associated properties are thought to contribute in several ways to cancer progression, genes identified in this study may represent novel targets for anti-cancer therapy.
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