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

Oncogene volume 30, pages 2161–2172 (2011)Cite this article

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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.

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Acknowledgements

Plasmids containing KLF4 specific shRNA (siKLF4), the control vector (siCon), KLF4 overexpression vector (KLF4-N) and the control vector (Control) were kindly provided by Daniel S Peeper at the Netherlands Cancer Institute. IAP reporter construct was provided by Dr Chunming Liu at the University of Texas Medical Branch. This work was partially supported by an NIH/NIDDK grant to WA (1K01DK069489).

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  1. F Yu and J Li: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, USA

    F Yu, J Li, S Ray, H Zheng & W Ai

  2. Centre for Stem Cell Research and Application, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    J Li & S Huang

  3. Department of Biological Sciences, University of South Carolina, Columbia, SC, USA

    H Chen & J Fu

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  1. F Yu
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Yu, F., Li, J., Chen, H. et al. Kruppel-like factor 4 (KLF4) is required for maintenance of breast cancer stem cells and for cell migration and invasion. Oncogene 30, 2161–2172 (2011). https://doi.org/10.1038/onc.2010.591

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