Metformin-Induced Killing of Triple-Negative Breast Cancer Cells Is Mediated by Reduction in Fatty Acid Synthase via miRNA-193b
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The anti-diabetic drug metformin (1,1-dimethylbiguanide hydrochloride) reduces both the incidence and mortality of several types of cancer. Metformin has been shown to selectively kill cancer stem cells, and triple-negative 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 metformin-treated 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 metformin-induced apoptosis. Profiling studies also exposed a rapid metformin-induced increase in miR-193 family members, and miR-193b directly targets the FASN 3′UTR. Addition of exogenous miR-193b mimic to untreated TNBC cells decreased FASN protein expression and increased apoptosis of TNBC cells, while spontaneously immortalized, non-transformed breast epithelial cells remained unaffected. Conversely, antagonizing miR-193 activity impaired the ability of metformin to decrease FASN and cause cell death. Further, the metformin-stimulated increase in miR-193 resulted in reduced mammosphere formation by TNBC lines. These studies provide mechanistic insight into metformin-induced killing of TNBC.
KeywordsMetformin Metformin Treatment TNBC Cell Mammosphere Formation TNBC Cell Line
This work was covered in part by the S. G. Komen Foundation for the Cure Grant K100575 to ADT, SMA, JKR, NIH P01 PAR-10-245 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.
Conflicts of Interest
No potential conflicts of interest were disclosed.
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