Epithelial transformation by KLF4 requires Notch1 but not canonical Notch1 signaling

• Published in: Cancer biology & therapy 2009-10, Vol.8 (19), p.1840-1851
• Main Authors: Liu, Zhaoli, Teng, Lihong, Bailey, Sarah, Frost, Andra R., Bland, Kirby I., LoBuglio, Albert F., Ruppert, J. Michael, Lobo-Ruppert, Susan M.
• Format: Article
• Language: English
• Subjects: Animals; Binding; Biology; Bioscience; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Calcium; Cancer; Cell; Cell Differentiation - physiology; Cell Growth Processes - physiology; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cycle; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Epithelial Cells - pathology; Female; Fluorescent Antibody Technique; Gene Expression Profiling; Gene Expression Regulation; Humans; Immunoblotting; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Landes; Mice; Oligonucleotide Array Sequence Analysis; Organogenesis; Proteins; Rats; Receptor, Notch1 - biosynthesis; Receptor, Notch1 - genetics; Receptor, Notch1 - metabolism; Signal Transduction; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 1538-4047; 1555-8576
• DOI: 10.4161/cbt.8.19.9440

The transcription factors Notch1 and KLF4 specify epithelial cell fates and confer stem cell properties.  Suggesting a functional relationship, each gene can act to promote or suppress tumorigenesis in a context-dependent manner, and alteration of KLF4 or Notch pathway genes in mice gives rise to similar phenotypes.  Activation of a conditional allele of KLF4 in RK3E epithelial cells rapidly induces expression of Notch1 mRNA and the active, intracellular form of Notch1.  KLF4-induced transformation was suppressed by knockdown of endogenous Notch1 using siRNA or an inhibitor of γ- secretase.  Chromatin immunoprecipitation assay shows that KLF4 binds to the proximal Notch1 promoter in human mammary epithelial cells, and siRNA-mediated suppression of KLF4 in human mammary cancer cells results in reduced expression of Notch1.  Furthermore, KLF4 and Notch1 expression are correlated in primary human breast tumors (N=89; Pearson analysis, r > 0.5, P