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

摘要

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