title: miR-206 Inhibits Stemness and Metastasis of Breast Cancer by Targeting MKL1/IL11 Pathway.
abstract: Purpose:Effective targeting of cancer stem cells is necessary and important for eradicating cancer and reducing metastasis-related mortality. Understanding of cancer stemness-related signaling pathways at the molecular level will help control cancer and stop metastasis in the clinic.Experimental Design:By analyzing miRNA profiles and functions in cancer development, we aimed to identify regulators of breast tumor stemness and metastasis in human xenograft modelsin vivoand examined their effects on self-renewal and invasion of breast cancer cellsin vitroTo discover the direct targets and essential signaling pathways responsible for miRNA functions in breast cancer progression, we performed microarray analysis and target gene prediction in combination with functional studies on candidate genes (overexpression rescues and pheno-copying knockdowns).Results:In this study, we report that hsa-miR-206 suppresses breast tumor stemness and metastasis by inhibiting both self-renewal and invasion. We identified that among the candidate targets, twinfilin (TWF1) rescues the miR-206 phenotype in invasion by enhancing the actin cytoskeleton dynamics and the activity of the mesenchymal lineage transcription factors, megakaryoblastic leukemia (translocation) 1 (MKL1), and serum response factor (SRF). MKL1 and SRF were further demonstrated to promote the expression ofIL11, which is essential for miR-206's function in inhibiting both invasion and stemness of breast cancer.Conclusions:The identification of the miR-206/TWF1/MKL1-SRF/IL11 signaling pathway sheds lights on the understanding of breast cancer initiation and progression, unveils new therapeutic targets, and facilitates innovative drug development to control cancer and block metastasis.Clin Cancer Res; 23(4); 1091-103. ©2016 AACR.
authors.affiliation: The Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois.
authors.forename: Ravand
authors.initials: R
authors.lastname: Samaeekia
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio.|Deparment of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Valery
authors.initials: V
authors.lastname: Adorno-Cruz
authors.affiliation: The Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois.|Stanford Cancer Institute, Stanford University, Stanford, California.
authors.forename: Jessica
authors.initials: J
authors.lastname: Bockhorn
authors.affiliation: The Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois.
authors.forename: Ya-Fang
authors.initials: YF
authors.lastname: Chang
authors.affiliation: Deparment of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Simo
authors.initials: S
authors.lastname: Huang
authors.affiliation: Translational Genomics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.|Department of Medical Oncology, Hospital Clínic, Universitat de Barcelona, Spain.
authors.forename: Aleix
authors.initials: A
authors.lastname: Prat
authors.affiliation: Deparment of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Nahun
authors.initials: N
authors.lastname: Ha
authors.affiliation: Deparment of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Golam
authors.initials: G
authors.lastname: Kibria
authors.affiliation: Department of Health Studies, The University of Chicago, Chicago, Illinois.
authors.forename: Dezheng
authors.initials: D
authors.lastname: Huo
authors.affiliation: Department of Mathematics, Statistics and Computer Science, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.affiliation: The Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois.
authors.forename: Rachel
authors.initials: R
authors.lastname: Dalton
authors.affiliation: The Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois.
authors.forename: Yuhao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois.
authors.forename: Grigoriy Y
authors.initials: GY
authors.lastname: Moskalenko
authors.affiliation: Deparment of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio. hliu@case.edu.|The Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.|The National Center for Regenerative Medicine, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Huiping
authors.initials: H
authors.lastname: Liu
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D017370:Interleukin-11 / Q000235:genetics*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008840:Microfilament Proteins / Q000235:genetics; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D026362:Serum Response Factor / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: C508611:IL11 protein, human; D017370:Interleukin-11; C546087:MIRN206 microRNA, human; C431575:MRTFA protein, human; D035683:MicroRNAs; D008840:Microfilament Proteins; C476858:SRF protein, human; D026362:Serum Response Factor; C485188:TWF1 protein, human; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases