title: MiR-155-mediated loss of C/EBPβ shifts the TGF-β response from growth inhibition to epithelial-mesenchymal transition, invasion and metastasis in breast cancer.
abstract: During breast cancer progression, transforming growth factor-beta (TGF-β) switches from acting as a growth inhibitor to become a major promoter of epithelial-mesenchymal transition (EMT), invasion and metastasis. However, the mechanisms involved in this switch are not clear. We found that loss of CCAAT-enhancer binding protein beta (C/EBPβ), a differentiation factor for the mammary epithelium, was associated with signs of EMT in triple-negative human breast cancer, and in invasive areas of mammary tumors in MMTV-PyMT mice. Using an established model of TGF-β-induced EMT in mouse mammary gland epithelial cells, we discovered that C/EBPβ was repressed during EMT by miR-155, an oncomiR in breast cancer. Depletion of C/EBPβ potentiated the TGF-β response towards EMT, and contributed to evasion of the growth inhibitory response to TGF-β. Furthermore, loss of C/EBPβ enhanced invasion and metastatic dissemination of the mouse mammary tumor cells to the lungs after subcutaneous injection into mice. The mechanism by which loss of C/EBPβ promoted the TGF-β response towards EMT, invasion and metastasis, was traced to a previously uncharacterized role of C/EBPβ as a transcriptional activator of genes encoding the epithelial junction proteins E-cadherin and coxsackie virus and adenovirus receptor. The results identify miR-155-mediated loss of C/EBPβ as a mechanism, which promotes breast cancer progression by shifting the TGF-β response from growth inhibition to EMT, invasion and metastasis.
authors: Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
authors: J
authors: J
authors: Johansson
authors: Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
authors: T
authors: T
authors: Berg
authors: 1] Department of Medicine, Centre for Molecular Medicine, Karolinska Institute, Stockholm, Sweden [2] Department of Internal Medicine, Medical University of Warsaw, Warsaw, Poland.
authors: E
authors: E
authors: Kurzejamska
authors: Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
authors: M-F
authors: MF
authors: Pang
authors: Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
authors: V
authors: V
authors: Tabor
authors: Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden.
authors: M
authors: M
authors: Jansson
authors: Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
authors: P
authors: P
authors: Roswall
authors: 1] Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden [2] Department of Laboratory Medicine Malmö, Lund University Cancer Center, Lund University, Malmö, Sweden.
authors: K
authors: K
authors: Pietras
authors: Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden.
authors: M
authors: M
authors: Sund
authors: Department of Medicine, Centre for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
authors: P
authors: P
authors: Religa
authors: Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
authors: J
authors: J
authors: Fuxe
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011485:Protein Binding; D034622:RNA Interference; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D016212:Transforming Growth Factor beta
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