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

Abstract

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.

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

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Acknowledgements

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.

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Correspondence to Roger H. Reeves.

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

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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). https://doi.org/10.1038/nature06446

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