title: Downregulation of CFTR promotes epithelial-to-mesenchymal transition and is associated with poor prognosis of breast cancer.
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.
authors.affiliation: Epithelial Cell Biology Research Center, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Jie Ting
authors.initials: JT
authors.lastname: Zhang
authors.affiliation: Epithelial Cell Biology Research Center, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong; Key Laboratory for Regenerative Medicine, Ji Nan University-The Chinese University of Hong Kong, Ministry of Education of The People's Republic of China, China.
authors.forename: Xiao Hua
authors.initials: XH
authors.lastname: Jiang
authors.affiliation: Epithelial Cell Biology Research Center, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Chen
authors.initials: C
authors.lastname: Xie
authors.affiliation: Department of Pathology, State Key Laboratory of Cancer Biology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Epithelial Cell Biology Research Center, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Jian
authors.initials: J
authors.lastname: Da Dong
authors.affiliation: Epithelial Cell Biology Research Center, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Epithelial Cell Biology Research Center, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Kin Lam
authors.initials: KL
authors.lastname: Fok
authors.affiliation: Epithelial Cell Biology Research Center, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Xiao Hu
authors.initials: XH
authors.lastname: Zhang
authors.affiliation: Epithelial Cell Biology Research Center, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Ting Ting
authors.initials: TT
authors.lastname: Sun
authors.affiliation: Epithelial Cell Biology Research Center, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Lai Ling
authors.initials: LL
authors.lastname: Tsang
authors.affiliation: Epithelial Cell Biology Research Center, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong; Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.affiliation: Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.
authors.forename: Xiao Juan
authors.initials: XJ
authors.lastname: Sun
authors.affiliation: Epithelial Cell Biology Research Center, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Yiu Wa
authors.initials: YW
authors.lastname: Chung
authors.affiliation: Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.
authors.forename: Zhi Ming
authors.initials: ZM
authors.lastname: Cai
authors.affiliation: Metastasis and Angiogenesis Research Group, Department of Surgery, Cardiff University School of Medicine, Cardiff, UK. Electronic address: jiangw@cf.ac.uk.
authors.forename: Wen Guo
authors.initials: WG
authors.lastname: Jiang
authors.affiliation: Epithelial Cell Biology Research Center, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong; Key Laboratory for Regenerative Medicine, Ji Nan University-The Chinese University of Hong Kong, Ministry of Education of The People's Republic of China, China; Sichuan University-The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, West China Second University Hospital, Chengdu, China. Electronic address: hsiaocchan@cuhk.edu.hk.
authors.forename: Hsiao Chang
authors.initials: HC
authors.lastname: Chan
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010641:Phenotype; D011379:Prognosis; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
chemical_list: C505032:CFTR protein, human; D016328:NF-kappa B; D053773:Transforming Growth Factor beta1; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D014568:Urokinase-Type Plasminogen Activator
keywords: Breast cancer; CFTR; Epithelial-to-mesenchymal transition (EMT); Prognosis; uPA