Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

Accession codes

Accessions

BINDPlus

References

  1. Liotta, L.A. & Stetler-Stevenson, W.G. Principles of Molecular Cell Biology of Cancer: Cancer Metastasis, 134–149 (J.B. Lippincott Co., Philadelphia, 1993).

    Google Scholar 

  2. Heimann, R., Lan, F., McBride, R. & Hellman, S. Separating favorable from unfavorable prognostic markers in breast cancer: the role of E-cadherin. Cancer Res. 60, 298–304 (2000).

    CAS  PubMed  Google Scholar 

  3. Guy, C.T., Cardiff, R.D. & Muller, W.J. Induction of mammary tumors by expression of polyomavirus middle T oncogene: A transgenic mouse model for metastatic disease. Mol. Cell. Biol. 12, 954–961 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lifsted, T. et al. Identification of inbred mouse strains harboring genetic modifiers of mammary tumor age of onset and metastatic progression. Int. J. Cancer 77, 640–644 (1998).

    Article  CAS  PubMed  Google Scholar 

  5. Hunter, K.W. et al. Predisposition to efficient mammary tumor metastatic progression is linked to the breast cancer metastasis suppressor gene Brms1. Cancer Res. 61, 8866–8872 (2001).

    CAS  PubMed  Google Scholar 

  6. Seraj, M.J., Samant, R.S., Verderame, M.F. & Welch, D.R. Functional evidence for a novel human breast carcinoma metastasis suppressor, BRMS1, encoded at chromosome 11q13. Cancer Res. 60, 2764–2769 (2000).

    CAS  PubMed  Google Scholar 

  7. Park, Y.G. et al. Comparative sequence analysis in eight inbred strains of the metastasis modifier QTL candidate gene Brms1. Mamm. Genome 13, 289–292 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Hitzemann, R. et al. Multiple cross mapping (MCM) markedly improves the localization of a QTL for ethanol-induced activation. Genes Brain Behav. 1, 214–222 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Wiltshire, T. et al. Genome-wide single-nucleotide polymorphism analysis defines haplotype patterns in mouse. Proc. Natl. Acad. Sci. USA 100, 3380–3385 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Park, Y.G., Clifford, R., Buetow, K.H. & Hunter, K.W. Multiple cross and inbred strain haplotype mapping of complex-trait candidate genes. Genome Res. 13, 118–121 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tsukamoto, N., Hattori, M., Yang, H., Bos, J.L. & Minato, N. Rap1 GTPase-activating protein SPA-1 negatively regulates cell adhesion. J. Biol. Chem. 274, 18463–18469 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Hitzemann, R. et al. A strategy for the integration of QTL, gene expression, and sequence analyses. Mamm. Genome 14, 733–747 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Steeg, P.S. Metastasis suppressors alter the signal transduction of cancer cells. Nat. Rev. Cancer 3, 55–63 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Bois, P. et al. Isolation and characterization of mouse minisatellites. Genomics 50, 317–330 (1998).

    Article  CAS  PubMed  Google Scholar 

  15. Nakamura, Y., Koyama, K. & Matsushima, M. VNTR (variable number of tandem repeat) sequences as transcriptional, translational, or functional regulators. J. Hum. Genet. 43, 149–152 (1998).

    Article  CAS  PubMed  Google Scholar 

  16. Bailly, S., Israel, N., Fay, M., Gougerot-Pocidalo, M.A. & Duff, G.W. An intronic polymorphic repeat sequence modulates interleukin-1 alpha gene regulation. Mol. Immunol. 33, 999–1006 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. van Ham, M. & Hendriks, W. PDZ domains-glue and guide. Mol. Biol. Rep. 30, 69–82 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Hogue, C.W. Cn3D: a new generation of three-dimensional molecular structure viewer. Trends Biochem. Sci. 22, 314–316 (1997).

    Article  CAS  PubMed  Google Scholar 

  19. Altschul, S.F. et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25, 3389–3402 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kurachi, H. et al. Human SPA-1 gene product selectively expressed in lymphoid tissues is a specific GTPase-activating protein for Rap1 and Rap2. Segregate expression profiles from a rap1GAP gene product. J. Biol. Chem. 272, 28081–28088 (1997).

    Article  CAS  PubMed  Google Scholar 

  21. Noda, Y. et al. Aquaporin-2 trafficking is regulated by PDZ-domain containing protein SPA-1. FEBS Lett. 568, 139–145 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Pei, X.F. et al. Explant-cell culture of primary mammary tumors from MMTV-c-Myc transgenic mice. In Vitro Cell. Dev. Biol. Anim. 40, 14–21 (2004).

    Article  PubMed  Google Scholar 

  23. Gao, Q., Srinivasan, S., Boyer, S.N., Wazer, D.E. & Band, V. The E6 oncoproteins of high-risk papillomaviruses bind to a novel putative GAP protein, E6TP1, and target it for degradation. Mol. Cell. Biol. 19, 733–744 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gould, K.A. et al. Genetic evaluation of candidate genes for the Mom1 modifier of intestinal neoplasia in mice. Genetics 144, 1777–1785 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Sledz, C.A., Holko, M., de Veer, M.J., Silverman, R.H. & Williams, B.R. Activation of the interferon system by short-interfering RNAs. Nat. Cell Biol. 5, 834–839 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Snove, O., Jr. & Holen, T. Many commonly used siRNAs risk off-target activity. Biochem. Biophys. Res. Commun. 319, 256–263 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Dhanasekaran, S.M. et al. Delineation of prognostic biomarkers in prostate cancer. Nature 412, 822–826 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. LaTulippe, E. et al. Comprehensive gene expression analysis of prostate cancer reveals distinct transcriptional programs associated with metastatic disease. Cancer Res. 62, 4499–4506 (2002).

    CAS  PubMed  Google Scholar 

  29. Bhattacharjee, A. et al. Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc. Natl. Acad. Sci. USA 98, 13790–13795 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Garber, M.E. et al. Diversity of gene expression in adenocarcinoma of the lung. Proc. Natl. Acad. Sci. USA 98, 13784–13789 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ramaswamy, S., Ross, K.N., Lander, E.S. & Golub, T.R. A molecular signature of metastasis in primary solid tumors. Nat. Genet. 33, 49–54 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Miele, M.E. et al. Metastasis suppressed, but tumorigenicity and local invasiveness unaffected, in the human melanoma cell line MelJuSo after introduction of human chromosomes 1 or 6. Mol. Carcinog. 15, 284–299 (1996).

    Article  CAS  PubMed  Google Scholar 

  33. Sekita, N. et al. Epigenetic regulation of the KAI1 metastasis suppressor gene in human prostate cancer cell lines. Jpn. J. Cancer Res. 92, 947–951 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Khanna, C. & Hunter, K. Modeling metastasis in vivo. Carcinogenesis 26, 513–523 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Pharoah, P.D. et al. Polygenic susceptibility to breast cancer and implications for prevention. Nat. Genet. 31, 33–36 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Day, N. et al. EPIC-Norfolk: study design and characteristics of the cohort. European prospective investigation of cancer. Br. J. Cancer 80 Suppl 1, 95–103 (1999).

    PubMed  Google Scholar 

  37. Hattori, M. et al. Molecular cloning of a novel mitogen-inducible nuclear protein with a Ran GTPase-activating domain that affects cell cycle progression. Mol. Cell. Biol. 15, 552–560 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ohba, Y. et al. Requirement for C3G-dependent Rap1 activation for cell adhesion and embryogenesis. EMBO J. 20, 3333–3341 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Yajnik, V. et al. DOCK4, a GTPase activator, is disrupted during tumorigenesis. Cell 112, 673–684 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Seftor, E.A. et al. Molecular determinants of human uveal melanoma invasion and metastasis. Clin. Exp. Metastasis 19, 233–246 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Stork, P.J. Does Rap1 deserve a bad Rap? Trends Biochem. Sci. 28, 267–275 (2003).

    Article  CAS  PubMed  Google Scholar 

  42. Farina, A. et al. Bromodomain protein Brd4 binds to GTPase-activating SPA-1, modulating its activity and subcellular localization. Mol. Cell. Biol. 24, 9059–9069 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ishida, D. et al. Myeloproliferative stem cell disorders by deregulated Rap1 activation in SPA-1-deficient mice. Cancer Cell 4, 55–65 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Hunter, K., Welch, D.R. & Liu, E.T. Genetic background is an important determinant of metastatic potential. Nat. Genet. 34, 23–24 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Hunter, K.W. Allelic diversity in the host genetic background may be an important determinant in tumor metastatic dissemination. Cancer Lett. 200, 97–105 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Hunter, K.W. Host genetics and tumour metastasis. Br. J. Cancer 90, 752–755 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gordon, D., Abajian, C. & Green, P. Consed: a graphical tool for sequence finishing. Genome Res. 8, 195–202 (1998).

    Article  CAS  PubMed  Google Scholar 

  48. Le Voyer, T. et al. An epistatic interaction controls the latency of a transgene-induced mammary tumor. Mamm. Genome 11, 883–889 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Hedenfalk, I. et al. Gene-expression profiles in hereditary breast cancer. N. Engl. J. Med. 344, 539–548 (2001).

    Article  CAS  PubMed  Google Scholar 

Download references

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

Authors
  1. Yeong-Gwan Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaohong Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fabienne Lesueur
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Douglas R Lowy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mindy Lancaster
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Paul Pharoah
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiaolan Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kent W Hunter
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kent W Hunter.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

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)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1635

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing