Article abstract
Nature Cell Biology 11, 1297 - 1304 (2009)
Published online: 4 October 2009 | doi:10.1038/ncb1974
KLF17 is a negative regulator of epithelial–mesenchymal transition and metastasis in breast cancer
Kiranmai Gumireddy1, Anping Li1, Phyllis A. Gimotty2, Andres J. Klein-Szanto3, Louise C. Showe1, Dionyssios Katsaros4, George Coukos5,6,7, Lin Zhang5,6 & Qihong Huang1
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.
- The Wistar Institute, 3601 Spruce Street, PA 19104, USA.
- Department of Biostatistics and Epidemiology, University of Pennsylvania, PA 19104, USA.
- Fox Chase Cancer Center, 333 Cottman Avenue, PA 19111-2497, USA.
- Department of Obstetrics and Gynecology, University of Turin, Turin, Italy.
- Center for Research on Early Detection and Cure of Ovarian Cancer, University of Pennsylvania, PA 19104, USA.
- Department of Obstetrics and Gynecology, University of Pennsylvania, PA 19104, USA.
- Abramson Family Cancer Research Institute, University of Pennsylvania, PA 19104, USA.
Correspondence to: Qihong Huang1 e-mail: qhuang@wistar.org
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