title: Nuclear factor I-C regulates E-cadherin via control of KLF4 in breast cancer.
abstract: BACKGROUND
  Progression to metastasis is the leading cause of most cancer-related mortality; however, much remains to be understood about what facilitates the spread of tumor cells. In the present study, we describe a novel pathway in breast cancer that regulates epithelial-to-mesenchymal transition (EMT), motility, and invasiveness.
  
  
  METHODS
  We examined nuclear factor I-C (NFI-C) expression in MCF10A human breast epithelial cells, MCF7 non-invasive breast cancer cells, and MDA-MB231 invasive breast cancer cells by real-time PCR and western blotting. To investigate the loss- and gain-function of NFI-C, we determined whether NFI-C regulated KLF4 expression by real-time PCR, western blotting, and promoter assay. To understand the biological functions of NFI-C, we observed cell invasion, migration, adhesion in human tumor cells by transwell assay, wound healing assay, quantitative RT-PCR, cell adhesion assay, western blotting, and immunohistochemistry.
  
  
  RESULTS
  We identified the downstream factors of NFI-C, such as KLF4 and E-cadherin, which play roles in EMT. NFI-C is expressed in normal mammary gland or noninvasive breast cancer cells with epithelial characteristics. NFI-C overexpression induced expression of KLF4 and E-cadherin, but not Slug, in breast cancer cells. NFI-C bound directly to the KLF4 promoter and stimulated KLF4 transcriptional activity, thereby regulating E-cadherin expression during tumorigenesis. Cells overexpressing NFI-C maintained their epithelial differentiation status, which could drive mesenchymal-epithelial transition (MET) via the NFI-C-KLF4-E-cadherin axis in breast cancer cells. Consequently, NFI-C suppressed EMT, migration, and invasion in breast cancer cells.
  
  
  CONCLUSIONS
  Our study reveals a novel signaling pathway that is important during breast cancer tumorigenesis: the NFI-C-KLF4-E-cadherin pathway. The results indicate the important role of NFI-C in regulating KLF4 during tumorigenesis.
authors: Department of Oral Histology-Developmental Biology & Dental Research Institute, School of Dentistry, Seoul National University, 101 Daehagro, Chongro-gu, Seoul, 110-749, South Korea. h35071221@snu.ac.kr.
authors: Hye-Kyung
authors: HK
authors: Lee
authors: Department of Oral Histology-Developmental Biology & Dental Research Institute, School of Dentistry, Seoul National University, 101 Daehagro, Chongro-gu, Seoul, 110-749, South Korea. iceburge@snu.ac.kr.
authors: Dong-Seol
authors: DS
authors: Lee
authors: Department of Oral Histology-Developmental Biology & Dental Research Institute, School of Dentistry, Seoul National University, 101 Daehagro, Chongro-gu, Seoul, 110-749, South Korea. jcapark@snu.ac.kr.
authors: Joo-Cheol
authors: JC
authors: Park
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015820:Cadherins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051839:NFI Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D015820:Cadherins; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D051839:NFI Transcription Factors; C497647:NFIC protein, human; C000594474:NFIX protein, human