Skip to main content

Thank you for visiting 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.

Trisomy represses ApcMin -mediated tumours in mouse models of Down’s syndrome


Epidemiological studies spanning more than 50 yr reach conflicting conclusions as to whether there is a lower incidence of solid tumours in people with trisomy 21 (Down’s syndrome)1,2. We used mouse models of Down’s syndrome and of cancer in a biological approach to investigate the relationship between trisomy and the incidence of intestinal tumours. ApcMin -mediated tumour number was determined in aneuploid mouse models Ts65Dn, Ts1Rhr and Ms1Rhr. Trisomy for orthologues of about half of the genes on chromosome 21 (Hsa21) in Ts65Dn mice or just 33 of these genes in Ts1Rhr mice resulted in a significant reduction in the number of intestinal tumours. In Ms1Rhr, segmental monosomy for the same 33 genes that are triplicated in Ts1Rhr resulted in an increased number of tumours. Further studies demonstrated that the Ets2 gene contributed most of the dosage-sensitive effect on intestinal tumour number. The action of Ets2 as a repressor when it is overexpressed differs from tumour suppression, which requires normal gene function to prevent cellular transformation. Upregulation of Ets2 and, potentially, other genes involved in this kind of protective effect may provide a prophylactic effect in all individuals, regardless of ploidy.

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

Access options

Rent or buy this article

Prices vary by article type



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

Figure 1: Ets2 dosage is substantially responsible for tumour number repression or increase.
Figure 2: Tumour growth and number are reduced in Ts65Dn mice.


  1. Satgé, D. et al. A tumor profile in Down syndrome. Am. J. Med. Genet. 78, 207–216 (1998)

    Article  Google Scholar 

  2. Yang, Q., Rasmussen, S. A. & Friedman, J. M. Mortality associated with Down's syndrome in the USA from 1983 to 1997: a population-based study. Lancet 359, 1019–1025 (2002)

    Article  Google Scholar 

  3. Reeves, R. H. et al. A mouse model for Down Syndrome exhibits learning and behaviour deficits. Nature Genet. 11, 177–183 (1995)

    Article  CAS  Google Scholar 

  4. Gardiner, K., Fortna, A., Bechtel, L. & Davisson, M. T. Mouse models of Down syndrome: how useful can they be? Comparison of the gene content of human chromosome 21 with orthologous mouse genomic regions. Gene 318, 137–147 (2003)

    Article  CAS  Google Scholar 

  5. Su, L. K. et al. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256, 668–670 (1992)

    Article  ADS  CAS  Google Scholar 

  6. Yamada, Y. & Mori, H. Multistep carcinogenesis of the colon in ApcMin/+) mouse. Cancer Sci. 98, 6–10 (2007)

    Article  CAS  Google Scholar 

  7. Dietrich, W. F. et al. Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse. Cell 75, 631–639 (1993)

    Article  CAS  Google Scholar 

  8. MacPhee, M. et al. The secretory phospholipase A2 gene is a candidate for the Mom1 locus, a major modifier of ApcMin -induced intestinal neoplasia. Cell 81, 957–966 (1995)

    Article  CAS  Google Scholar 

  9. Olson, L. E., Richtsmeier, J. T., Leszl, J. & Reeves, R. H. A chromosome 21 critical region does not cause specific Down syndrome phenotypes. Science 306, 687–690 (2004)

    Article  ADS  CAS  Google Scholar 

  10. Hsu, T., Trojanowska, M. & Watson, D. K. Ets proteins in biological control and cancer. J. Cell. Biochem. 91, 896–903 (2004)

    Article  CAS  Google Scholar 

  11. Wolvetang, E. J. et al. Overexpression of the chromosome 21 transcription factor Ets2 induces neuronal apoptosis. Neurobiol. Dis. 14, 349–356 (2003)

    Article  CAS  Google Scholar 

  12. Roberts, R. B. et al. Importance of epidermal growth factor receptor signaling in establishment of adenomas and maintenance of carcinomas during intestinal tumorigenesis. Proc. Natl Acad. Sci. USA 99, 1521–1526 (2002)

    Article  ADS  CAS  Google Scholar 

  13. Day, S. M., Strauss, D. J., Shavelle, R. M. & Reynolds, R. J. Mortality and causes of death in persons with Down syndrome in California. Dev. Med. Child Neurol. 47, 171–176 (2005)

    Article  Google Scholar 

  14. Hill, D. A. et al. Mortality and cancer incidence among individuals with Down syndrome. Arch. Intern. Med. 163, 705–711 (2003)

    Article  Google Scholar 

  15. Patja, K., Pukkala, E., Sund, R., Iivanainen, M. & Kaski, M. Cancer incidence of persons with Down syndrome in Finland: a population-based study. Int. J. Cancer 118, 1769–1772 (2006)

    Article  CAS  Google Scholar 

  16. Goldacre, M. J., Wotton, C. J., Seagroatt, V. & Yeates, D. Cancers and immune related diseases associated with Down's syndrome: a record linkage study. Arch. Dis. Child. 89, 1014–1017 (2004)

    Article  CAS  Google Scholar 

  17. O'Reilly, M. S. et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88, 277–285 (1997)

    Article  CAS  Google Scholar 

  18. Minami, T. et al. Vascular endothelial growth factor- and thrombin-induced termination factor, Down syndrome critical region-1, attenuates endothelial cell proliferation and angiogenesis. J. Biol. Chem. 279, 50537–50554 (2004)

    Article  CAS  Google Scholar 

  19. Moore, C. S. et al. Integration of cytogenetic with recombinational and physical maps of mouse chromosome 16. Genomics 59, 1–5 (1999)

    Article  CAS  Google Scholar 

  20. The Jackson Laboratory. Genotyping protocol for Apc. 〈 &protocol_id=529#133

  21. Smith, J. L. et al. ets-2 is a target for an akt (Protein kinase B)/jun N-terminal kinase signaling pathway in macrophages of motheaten-viable mutant mice. Mol. Cell. Biol. 20, 8026–8034 (2000)

    Article  CAS  Google Scholar 

Download references


The authors thank L. Siracusa for advice regarding the ApcMin system, C. Dang for important discussions regarding cancer models, and R. Roper for statistical advice. This work was supported by National Institute of Child Health and Development and National Cancer Institute awards (M.C.O. and R.H.R.).

Author Contributions T.E.S. and R.H.R. designed the experiments. T.E.S. and A.Y. managed husbandry and collected tumour data, which were analysed by T.E.S., A.Y. and R.H.R.; F.L. and M.C.O. designed the Ets2 conditional knockout mice; and A.Y., F.L. and M.C.O. analysed Ets2 expression. R.H.R. wrote the paper with substantial input from all authors.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Roger H. Reeves.

Supplementary information

Supplementary Information

The file contains Supplementary Tables 1-2 and Supplementary Figures 1-4 with Legends. (PDF 319 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sussan, T., Yang, A., Li, F. et al. Trisomy represses ApcMin -mediated tumours in mouse models of Down’s syndrome. Nature 451, 73–75 (2008).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


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