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
Författare
Summary, in 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.
Avdelning/ar
Publiceringsår
2013
Språk
Engelska
Sidor
5614-5624
Publikation/Tidskrift/Serie
Oncogene
Volym
32
Issue
50
Dokumenttyp
Artikel i tidskrift
Förlag
Nature Publishing Group
Ämne
- Cancer and Oncology
Nyckelord
- CCAAT-enhancer binding protein beta
- epithelial-mesenchymal transition
- transforming growth factor-beta
- Breast cancer
- metastasis
Status
Published
ISBN/ISSN/Övrigt
- ISSN: 1476-5594