Oncotarget

Research Papers:

Genome-wide functional genetic screen with the anticancer agent AMPI-109 identifies PRL-3 as an oncogenic driver in triple-negative breast cancers

Hamid H. Gari, Christy M. Gearheart, Susan Fosmire, Gregory D. DeGala, Zeying Fan, Kathleen C. Torkko, Susan M. Edgerton, M. Scott Lucia, Rahul Ray, Ann D. Thor, Christopher C. Porter and James R. Lambert _

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Oncotarget. 2016; 7:15757-15771. https://doi.org/10.18632/oncotarget.7462

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Abstract

Hamid H. Gari1, Christy M. Gearheart2, Susan Fosmire2, Gregory D. DeGala1, Zeying Fan1, Kathleen C. Torkko1, Susan M. Edgerton1, M. Scott Lucia1, Rahul Ray3, Ann D. Thor1, Christopher C. Porter2 and James R. Lambert1

1 Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA

2 Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA

3 Department of Medicine, Boston University School of Medicine, Boston, MA, USA

Correspondence to:

James R. Lambert, email:

Keywords: AMPI-109, PRL-3, triple-negative breast cancer, phosphatase, functional genomics

Received: December 22, 2015 Accepted: February 09, 2016 Published: February 17, 2016

Abstract

Triple-negative breast cancers (TNBC) are among the most aggressive and heterogeneous cancers with a high propensity to invade, metastasize and relapse. Here, we demonstrate that the anticancer compound, AMPI-109, is selectively efficacious in inhibiting proliferation and inducing apoptosis of multiple TNBC subtype cell lines as assessed by activation of pro-apoptotic caspases-3 and 7, PARP cleavage and nucleosomal DNA fragmentation. AMPI-109 had little to no effect on growth in the majority of non-TNBC cell lines examined. We therefore utilized AMPI-109 in a genome-wide shRNA screen in the TNBC cell line, BT-20, to investigate the utility of AMPI-109 as a tool in helping to identify molecular alterations unique to TNBC. Our screen identified the oncogenic phosphatase, PRL-3, as a potentially important driver of TNBC growth, migration and invasion. Through stable lentiviral knock downs and transfection with catalytically impaired PRL-3 in TNBC cells, loss of PRL-3 expression, or functionality, led to substantial growth inhibition. Moreover, AMPI-109 treatment, downregulation of PRL-3 expression or impairment of PRL-3 activity reduced TNBC cell migration and invasion. Histological evaluation of human breast cancers revealed PRL-3 was significantly, though not exclusively, associated with the TNBC subtype and correlated positively with regional and distant metastases, as well as 1 and 3 year relapse free survival. Collectively, our study is proof-of-concept that AMPI-109, a selectively active agent against TNBC cell lines, can be used as a molecular tool to uncover unique drivers of disease progression, such as PRL-3, which we show promotes oncogenic phenotypes in TNBC cells.


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