title: miR-34a Silences c-SRC to Attenuate Tumor Growth in Triple-Negative Breast Cancer.
abstract: Triple-negative breast cancer (TNBC) is an aggressive subtype with no clinically proven biologically targeted treatment options. The molecular heterogeneity of TNBC and lack of high frequency driver mutations other than TP53 have hindered the development of new and effective therapies that significantly improve patient outcomes. miRNAs, global regulators of survival and proliferation pathways important in tumor development and maintenance, are becoming promising therapeutic agents. We performed miRNA-profiling studies in different TNBC subtypes to identify miRNAs that significantly contribute to disease progression. We found that miR-34a was lost in TNBC, specifically within mesenchymal and mesenchymal stem cell-like subtypes, whereas expression of miR-34a targets was significantly enriched. Furthermore, restoration of miR-34a in cell lines representing these subtypes inhibited proliferation and invasion, activated senescence, and promoted sensitivity to dasatinib by targeting the proto-oncogene c-SRC. Notably, SRC depletion in TNBC cell lines phenocopied the effects of miR-34a reintroduction, whereas SRC overexpression rescued the antitumorigenic properties mediated by miR-34a. miR-34a levels also increased when cells were treated with c-SRC inhibitors, suggesting a negative feedback exists between miR-34a and c-SRC. Moreover, miR-34a administration significantly delayed tumor growth of subcutaneously and orthotopically implanted tumors in nude mice, and was accompanied by c-SRC downregulation. Finally, we found that miR-34a and SRC levels were inversely correlated in human tumor specimens. Together, our results demonstrate that miR-34a exerts potent antitumorigenic effects in vitro and in vivo and suggests that miR-34a replacement therapy, which is currently being tested in human clinical trials, represents a promising therapeutic strategy for TNBC.
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Adams
authors.affiliation: Yale Cancer Center Genetics and Genomics Program, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Vikram B
authors.initials: VB
authors.lastname: Wali
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut. Department of Biomedical Engineering, Yale University, New Haven, Connecticut.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Cheng
authors.affiliation: Institute for RNA Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Sachi
authors.initials: S
authors.lastname: Inukai
authors.affiliation: Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Carmen J
authors.initials: CJ
authors.lastname: Booth
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Seema
authors.initials: S
authors.lastname: Agarwal
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: David L
authors.initials: DL
authors.lastname: Rimm
authors.affiliation: 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary. MTA TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Győrffy
authors.affiliation: Humanitas Clinical and Research Institute, Rozzano, Milan, Italy.
authors.forename: Libero
authors.initials: L
authors.lastname: Santarpia
authors.affiliation: Yale Cancer Center Genetics and Genomics Program, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Lajos
authors.initials: L
authors.lastname: Pusztai
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, Connecticut.
authors.forename: W Mark
authors.initials: WM
authors.lastname: Saltzman
authors.affiliation: Institute for RNA Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. fslack@bidmc.harvard.edu.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Slack
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D064726:Triple Negative Breast Neoplasms / Q000235:genetics; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: C000715470:MAS1 protein, human; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D000090063:Proto-Oncogene Mas; D019061:src-Family Kinases