KLF17 is a negative regulator of epithelial–mesenchymal transition and metastasis in breast cancer

Abstract

Metastasis is a complex multistep process, which requires the concerted action of many genes and is the primary cause of cancer death. Both pathways that regulate metastasis enhancement and those that regulate its suppression contribute to the tumour dissemination process. To identify new metastasis suppressors, we set up a forward genetic screen in a mouse model. We transduced a genome-wide RNA interference (RNAi) library into the non-metastatic 168FARN breast cancer cell line and orthotopically transplanted the cells into mouse mammary fat pads. We then selected cells that could metastasize to the lung and identified an RNAi for the KLF17 gene. Conversely, we demonstrate that ectopic expression of KLF17 in a highly metastatic 4T1 breast cancer cell line inhibits the ability of cells to metastasize from the mammary fat pad to the lung. We also show that suppression of KLF17 expression promotes breast cancer cell invasion and epithelial–mesenchymal transition (EMT), and that KLF17 protein functions by directly binding to the promoter region of Id1 (which encodes a key metastasis regulator in breast cancer) to inhibit its transcription. Finally, we demonstrate that KLF17 expression is significantly downregulated in primary human breast cancer samples and that the combined expression pattern of KLF17 and Id1 can serve as a potential biomarker for lymph node metastasis in breast cancer.

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Figure 1: Identification of KLF17 as a metastasis-suppressing gene.
Figure 2: KLF17 suppresses tumour metastasis in vivo.
Figure 3: Suppression of KLF17 expression promotes tumour cell migration, invasion and EMT.
Figure 4: KLF17 directly binds to the promoter of Id1 and suppresses Id1 expression.
Figure 5: KLF17 and Id1 expression in breast cancer cell lines and their predictive value of lymph node metastasis in human primary breast cancer samples.

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Acknowledgements

We would like to thank F. Miller for providing 168FARN and 4T1 cells, R. Weinberg for providing the HMEL cell line, J. Price for providing the MDA-MB-435 cell line, C. Chang and W. Horng for assistance with microarray analysis and J. Hayden and F. Keeney for assistance with microscopy. Q.H. is supported by the Breast Cancer Alliance, Pardee Foundation, V Foundation. Q.H. and L.C.S. are supported by the Commonwealth Universal Research Enhancement Program, Pennsylvania Department of Health (PA DOH; P30 CA10815) and L.C.S. is supported by a PA DOH grant (SAP 4100020718). G.C. and L.Z. are supported by NCI ovarian SPORE (P50-CA83638), Ovarian Cancer Research Fund and Mary Kay Ash Charitable Foundation.

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K.G. and Q. H. designed the experiments. K.G and A.L. performed the experiments. P.A.G. performed statistical analysis. A.J.K. performed pathological analysis. D.K., G.C. and L.Z. provided experimental materials. K.G., A.L., L.C.S and Q.H. analysed data. K.G., L.C.S. and Q.H. prepared the manuscript.

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Correspondence to Qihong Huang.

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The authors declare no competing financial interests.

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Gumireddy, K., Li, A., Gimotty, P. et al. KLF17 is a negative regulator of epithelial–mesenchymal transition and metastasis in breast cancer. Nat Cell Biol 11, 1297–1304 (2009). https://doi.org/10.1038/ncb1974

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