Abstract
The Krüppel-like factor 4 (KLF4) is a transcriptional regulator of proliferation and differentiation in epithelial cells, both during development and tumorigenesis. Although KLF4 functions as a tumor suppressor in several tissues, including the colon, the role of KLF4 in breast cancer is less clear. Here, we show that KLF4 is necessary for maintenance of the epithelial phenotype in non-transformed MCF-10A mammary epithelial cells. KLF4 silencing led to alterations in epithelial cell morphology and migration, indicative of an epithelial-to-mesenchymal transition. Consistent with these changes, decreased levels of KLF4 also resulted in the loss of E-cadherin protein and mRNA. Promoter/reporter analyses revealed decreased E-cadherin promoter activity with KLF4 silencing, while chromatin immunoprecipitation identified endogenous KLF4 binding to the GC-rich/E-box region of this promoter. Furthermore, forced expression of KLF4 in the highly metastatic MDA-MB-231 breast tumor cell line was sufficient to restore E-cadherin expression and suppress migration and invasion. These findings identify E-cadherin as a novel transcriptional target of KLF4. The clear requirement for KLF4 to maintain E-cadherin expression and prevent epithelial-to-mesenchymal transition in mammary epithelial cells supports a metastasis suppressive role for KLF4 in breast cancer.
Highlights
Kruppel-like factor 4 (KLF4)3 is a zinc finger transcription factor that was first identified in a screen for transcription factors involved in growth regulation [1]
We show that forced expression of KLF4 in the highly metastatic MDA-MB231 breast cancer cell line restores E-cadherin expression, resulting in reduced migration and invasion
KLF4 Is Required for the Maintenance of Mammary Epithelial Cell Morphology—To directly assess the role of KLF4 in non-transformed mammary epithelial cells, we used lentiviral and retroviral vector-mediated Short hairpin RNAs (shRNAs) to create stable MCF10A cell lines with suppressed KLF4 expression
Summary
Kruppel-like factor 4 (KLF4)3 is a zinc finger transcription factor that was first identified in a screen for transcription factors involved in growth regulation [1]. The clear requirement for KLF4 to maintain E-cadherin expression and prevent epithelial-to-mesenchymal transition in mammary epithelial cells supports a metastasis suppressive role for KLF4 in breast cancer.
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