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Sipa1 is a candidate for underlying the metastasis efficiency modifier locus Mtes1

Nature Genetics volume 37, pages 1055–1062 (2005)Cite this article

Abstract

We previously identified loci in the mouse genome that substantially influence the metastatic efficiency of mammary tumors. Here, we present data supporting the idea that the signal transduction molecule, Sipa1, is a candidate for underlying the metastasis efficiency modifier locus Mtes1. Analysis of candidate genes identified a nonsynonymous amino acid polymorphism in Sipa1 that affects the Sipa1 Rap-GAP function. Spontaneous metastasis assays using cells ectopically expressing Sipa1 or cells with knocked-down Sipa1 expression showed that metastatic capacity was correlated with cellular Sipa1 levels. We examined human expression data and found that they were consistent with the idea that Sipa1 concentration has a role in metastasis. Taken together, these data suggest that the Sipa1 polymorphism is one of the genetic polymorphisms underlying the Mtes1 locus. This report is also the first demonstration, to our knowledge, of a constitutional genetic polymorphism affecting tumor metastasis.

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Figure 1: Analysis of the Sipa1 candidate region.
Figure 2: The A739T polymorphism affects complex formation with AQP2 and the Rap-GAP function of Sipa1 in an AQP2-dependent manner.
Figure 3: shRNA knock-down of Sipa1.
Figure 4: Results of shRNA analysis.
Figure 5: Morphology of the shRNA cell line.
Figure 6: Scatter plot of the lung surface metastasis counts of mice implanted with cells ectopically overexpressing Sipa1.
Figure 7: Graphical results of the Oncomine meta-analysis.

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Acknowledgements

We thank B. Ponder and the members of the Laboratory of Population Genetics for discussions and A. Papageorge and V. Bliskovsky for technical assistance and discussions. This research was supported in part by the Intramural Research Program of the US National Institutes of Health, the US National Cancer Institute and the Center for Cancer Research.

Author information

Author notes

  1. Yeong-Gwan Park

    Present address: Exam. Div. of Food & Biological Resources, Korean Intellectual Property Office, Room 903, Gov. Complex Daejeon Building 4, 130 Seonsaro, Seo-gu, Daejeon, 302-701, Korea

  2. Fabienne Lesueur

    Present address: C.N.R.G., 2 rue Gaston Cremieux, CP 5721, 91057, Evry Cedex, France

  3. Yeong-Gwan Park and Xiaohong Zhao: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Population Genetics, National Cancer Institute, Building 41, Room 702, 41 Library Drive, Bethesda, 20892, Maryland, USA

    Yeong-Gwan Park, Xiaohong Zhao, Mindy Lancaster & Kent W Hunter

  2. Department of Oncology, University of Cambridge, Hutchinson/MRC Research Centre, Hills Road, Cambridge, CB2 2XZ, UK

    Fabienne Lesueur & Paul Pharoah

  3. Laboratory of Cellular Oncology, National Cancer Institute, Bethesda, 20892, Maryland, USA

    Douglas R Lowy & Xiaolan Qian

  4. Exam. Div. of Food & Biological Resources, Korean Intellectual Property Office, Room 903, Gov. Complex Daejeon Building 4, 130 Seonsaro, Seo-gu, Daejeon, 302-701, Korea

    Fabienne Lesueur

  5. C.N.R.G., 2 rue Gaston Cremieux, CP 5721, 91057, Evry Cedex, France

    Yeong-Gwan Park

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Supplementary information

Supplementary Table 1

Genes differentially expressed between RNAi and control cell lines. (XLS 56 kb)

Supplementary Table 2

Oligos used in this study. (PDF 8 kb)

Supplementary Note (PDF 9 kb)

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Park, YG., Zhao, X., Lesueur, F. et al. Sipa1 is a candidate for underlying the metastasis efficiency modifier locus Mtes1. Nat Genet 37, 1055–1062 (2005). https://doi.org/10.1038/ng1635

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