MetforminInduced Killing of TripleNegative Breas

Authors: Reema S WahdanAlaswad Dawn R Cochrane Nicole S Spoelstra Erin N Howe Susan M Edgerton Steven M Anderson Ann D Thor Jennifer K Richer

Publish Date: 2014/09/12

Volume: 5, Issue: 6, Pages: 374-389

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Abstract

The antidiabetic drug metformin 11dimethylbiguanide hydrochloride reduces both the incidence and mortality of several types of cancer Metformin has been shown to selectively kill cancer stem cells and triplenegative breast cancer TNBC cell lines are more sensitive to the effects of metformin as compared to luminal breast cancer However the mechanism underlying the enhanced susceptibility of TNBC to metformin has not been elucidated Expression profiling of metformintreated TNBC lines revealed fatty acid synthase FASN as one of the genes most significantly downregulated following 24 h of treatment and a decrease in FASN protein was also observed Since FASN is critical for de novo fatty acid synthesis and is important for the survival of TNBC we hypothesized that FASN downregulation facilitates metformininduced apoptosis Profiling studies also exposed a rapid metformininduced increase in miR193 family members and miR193b directly targets the FASN 3′UTR Addition of exogenous miR193b mimic to untreated TNBC cells decreased FASN protein expression and increased apoptosis of TNBC cells while spontaneously immortalized nontransformed breast epithelial cells remained unaffected Conversely antagonizing miR193 activity impaired the ability of metformin to decrease FASN and cause cell death Further the metforminstimulated increase in miR193 resulted in reduced mammosphere formation by TNBC lines These studies provide mechanistic insight into metformininduced killing of TNBCThis work was covered in part by the S G Komen Foundation for the Cure Grant K100575 to ADT SMA JKR NIH P01 PAR10245 to SMA and the AMC Women’s Cancer Fund/Salah Foundation JKR We also acknowledge the following University of Colorado Cancer Center Shared Resource facilities supported by NIH/NCI P30CA046934 the DNA Sequencing and Analysis Shared Resource the Microarray Shared Resource the Flow Cytometry Shared Resource and the Protein Production Monoclonal antibody and Tissue Culture Shared Resource

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