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MiR-155-mediated loss of C/EBP beta shifts the TGF-beta response from growth inhibition to epithelial-mesenchymal transition, invasion and metastasis in breast cancer

Author:
  • J. Johansson
  • T. Berg
  • E. Kurzejamska
  • M-F Pang
  • V. Tabor
  • M. Jansson
  • P. Roswall
  • Kristian Pietras
  • M. Sund
  • P. Religa
  • J. Fuxe
Publishing year: 2013
Language: English
Pages: 5614-5624
Publication/Series: Oncogene
Volume: 32
Issue: 50
Document type: Journal article
Publisher: Nature Publishing Group

Abstract english

During breast cancer progression, transforming growth factor-beta (TGF-beta) 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/EBP beta), 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-beta-induced EMT in mouse mammary gland epithelial cells, we discovered that C/EBP beta was repressed during EMT by miR-155, an oncomiR in breast cancer. Depletion of C/EBP beta potentiated the TGF-beta response towards EMT, and contributed to evasion of the growth inhibitory response to TGF-beta. Furthermore, loss of C/EBP beta 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/EBP beta promoted the TGF-beta response towards EMT, invasion and metastasis, was traced to a previously uncharacterized role of C/EBP beta 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/EBP beta as a mechanism, which promotes breast cancer progression by shifting the TGF-beta response from growth inhibition to EMT, invasion and metastasis.

Keywords

  • Cancer and Oncology
  • CCAAT-enhancer binding protein beta
  • epithelial-mesenchymal transition
  • transforming growth factor-beta
  • Breast cancer
  • metastasis

Other

Published
  • ISSN: 1476-5594
Kristian Pietras
E-mail: kristian [dot] pietras [at] med [dot] lu [dot] se

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Division of Translational Cancer Research

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Experimental oncology