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Downregulation of CFTR promotes epithelial-to-mesenchymal transition and is associated with poor prognosis of breast cancer

Zhang, Jie Ting, Jiang, Xiao Hua, Xie, Chen, Cheng, Hong, Da Dong, Jian, Wang, Yan, Fok, Kin Lam, Zhang, Xiao Hu, Sun, Ting Ting, Tsang, Lai Ling, Chen, Hao, Sun, Xiao Juan, Chung, Yiu Wa, Cai, Zhi Ming, Jiang, Wen Guo and Chan, Hsiao Chang 2013. Downregulation of CFTR promotes epithelial-to-mesenchymal transition and is associated with poor prognosis of breast cancer. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1833 (12) , pp. 2961-2969. 10.1016/j.bbamcr.2013.07.021

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Abstract

The epithelial-to-mesenchymal transition (EMT), a process involving the breakdown of cell–cell junctions and loss of epithelial polarity, is closely related to cancer development and metastatic progression. While the cystic fibrosis transmembrane conductance regulator (CFTR), a Cl− and HCO3− conducting anion channel expressed in a wide variety of epithelial cells, has been implicated in the regulation of epithelial polarity, the exact role of CFTR in the pathogenesis of cancer and its possible involvement in EMT process have not been elucidated. Here we report that interfering with CFTR function either by its specific inhibitor or lentiviral miRNA-mediated knockdown mimics TGF-β1-induced EMT and enhances cell migration and invasion in MCF-7. Ectopic overexpression of CFTR in a highly metastatic MDA-231 breast cancer cell line downregulates EMT markers and suppresses cell invasion and migration in vitro, as well as metastasis in vivo. The EMT-suppressing effect of CFTR is found to be associated with its ability to inhibit NFκB targeting urokinase-type plasminogen activator (uPA), known to be involved in the regulation of EMT. More importantly, CFTR expression is found significantly downregulated in primary human breast cancer samples, and is closely associated with poor prognosis in different cohorts of breast cancer patients. Taken together, the present study has demonstrated a previously undefined role of CFTR as an EMT suppressor and its potential as a prognostic indicator in breast cancer.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: Epithelial-to-mesenchymal transition (EMT); CFTR; Breast cancer; Prognosis; uPA
Publisher: Elsevier
ISSN: 0167-4889
Date of Acceptance: 24 July 2013
Last Modified: 04 Jun 2017 08:13
URI: http://orca-mwe.cf.ac.uk/id/eprint/74392

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