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PMID: 21242971 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Kruppel-like factor 4 (KLF4) is required for maintenance of breast cancer stem cells and for cell migration and invasion.

Oncogene ·Vol. 30 ·No. 18 ·2011-05-05 ·Pages 2161-72

Yu F, Li J, Chen H, Fu J, Ray S, Huang S, Zheng H, Ai W

Abstract

Kruppel-like factor 4 (KLF4) is highly expressed in more than 70% of breast cancers and functions as an oncogene. However, an exact mechanism by which KLF4 enhances tumorigenesis of breast cancer remains unknown. In this study, we show that KLF4 was highly expressed in cancer stem cell (CSC)-enriched populations in mouse primary mammary tumor and breast cancer cell lines. Knockdown of KLF4 in breast cancer cells (MCF-7 and MDA-MB-231) decreased the proportion of stem/progenitor cells as demonstrated by expression of stem cell surface markers such as aldehyde dehydrogenase 1, side population and by in vitro mammosphere assay. Consistently KLF4 overexpression led to an increase of the cancer stem cell population. KLF4 knockdown also suppressed cell migration and invasion in MCF-7 and MDA-MB-231 cells. Furthermore, knockdown of KLF4 reduced colony formation in vitro and inhibited tumorigenesis in immunocompromised non-obese diabetic/severe combined immunodeficiency mice, supporting an oncogenic role for KLF4 in breast cancer development. Further mechanistic studies revealed that the Notch signaling pathway was required for KLF4-mediated cell migration and invasion, but not for CSC maintenance. Taken together, our study provides evidence that KLF4 has a potent oncogenic role in mammary tumorigenesis likely by maintaining stem cell-like features and by promoting cell migration and invasion. Thus, targeting KLF4 may provide an effective therapeutic approach to suppress tumorigenicity in breast cancer.

MeSH Terms
Breast Neoplasms/pathology,physiopathology Cell Line, Tumor Gene Knockdown Techniques Humans Kruppel-Like Factor 4 Kruppel-Like Transcription Factors/genetics,physiology Neoplasm Invasiveness Neoplasm Metastasis Neoplastic Stem Cells/cytology Receptors, Notch/metabolism Signal Transduction
Chemicals
KLF4 protein, human Klf4 protein, mouse Kruppel-Like Factor 4 Kruppel-Like Transcription Factors Receptors, Notch
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Yu F
Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, USA.
Li J
Chen H
Fu J
Ray S
Huang S
Zheng H
Ai W
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Article Info
Journal
Oncogene
Abbr.
Oncogene
ISSN
1476-5594
DOI
10.1038/onc.2010.591
Published
2011-05-05
Epub
2011-00-17
Pages
2161-72
Language
English
Region
England
NLM ID
8711562
PMCID
PMC3088782
Subset
IM
Grants
NIDDK NIH HHS · K01 DK069489 · United States
NIDDK NIH HHS · K01 DK069489-05 · United States
NIAMS NIH HHS · R03 AR060987 · United States
NIDDK NIH HHS · 1K01DK069489 · United States
External Links
PubMed source DOI: 10.1038/onc.2010.591 PMC Full Text View journal details
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