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

被引：143

作者：

Johansson, J. ^{[1
]}

Berg, T. ^{[1
]}

Kurzejamska, E. ^{[2
,3
]}

Pang, M-F ^{[1
]}

Tabor, V. ^{[1
]}

Jansson, M. ^{[4
]}

Roswall, P. ^{[1
]}

Pietras, K. ^{[1
,5
]}

Sund, M. ^{[4
]}

Religa, P. ^{[2
]}

Fuxe, J. ^{[1
]}

机构：

[1] Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, S-17177 Stockholm, Sweden

[2] Karolinska Inst, Dept Med, Ctr Mol Med, S-17177 Stockholm, Sweden

[3] Med Univ Warsaw, Dept Internal Med, Warsaw, Poland

[4] Umea Univ, Dept Surg & Perioperat Sci, Umea, Sweden

[5] Lund Univ, Dept Lab Med Malmo, Ctr Canc, Malmo, Sweden

来源：

ONCOGENE | 2013年 / 32卷 / 50期

基金：

瑞典研究理事会;

关键词：

CCAAT-enhancer binding protein beta; epithelial-mesenchymal transition; transforming growth factor-beta; Breast cancer; metastasis; BINDING-PROTEIN-BETA; BONE MORPHOGENETIC PROTEIN-7; CELL-PROLIFERATION; TARGETING RHOA; MAMMARY-GLAND; C-MYC; TUMOR; SMAD; REPRESSION; PLASTICITY;

D O I：

10.1038/onc.2013.322

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：5614 / 5624

页数：11

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