title: Metformin-induced killing of triple-negative breast cancer cells is mediated by reduction in fatty acid synthase via miRNA-193b.
abstract: 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.
authors.affiliation: Department of Pathology, University of Colorado Anschutz Medical Campus, Mail Stop 8104, Aurora, CO, 80045, USA.
authors.forename: Reema S
authors.initials: RS
authors.lastname: Wahdan-Alaswad
authors.forename: Dawn R
authors.initials: DR
authors.lastname: Cochrane
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Spoelstra
authors.forename: Erin N
authors.initials: EN
authors.lastname: Howe
authors.forename: Susan M
authors.initials: SM
authors.lastname: Edgerton
authors.forename: Steven M
authors.initials: SM
authors.lastname: Anderson
authors.forename: Ann D
authors.initials: AD
authors.lastname: Thor
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Richer
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D054890:Fatty Acid Synthase, Type I / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D042361:Mammary Glands, Human / Q000187:drug effects; D008687:Metformin / Q000627:therapeutic use*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D020413:3' Untranslated Regions; C546818:MIRN193 microRNA, human; D035683:MicroRNAs; D008687:Metformin; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I