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Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1

Abstract

The incidence of many cancer types is significantly reduced in individuals with Down’s syndrome1,2,3,4, and it is thought that this broad cancer protection is conferred by the increased expression of one or more of the 231 supernumerary genes on the extra copy of chromosome 21. One such gene is Down’s syndrome candidate region-1 (DSCR1, also known as RCAN1), which encodes a protein that suppresses vascular endothelial growth factor (VEGF)-mediated angiogenic signalling by the calcineurin pathway5,6,7,8,9,10. Here we show that DSCR1 is increased in Down’s syndrome tissues and in a mouse model of Down’s syndrome. Furthermore, we show that the modest increase in expression afforded by a single extra transgenic copy of Dscr1 is sufficient to confer significant suppression of tumour growth in mice, and that such resistance is a consequence of a deficit in tumour angiogenesis arising from suppression of the calcineurin pathway. We also provide evidence that attenuation of calcineurin activity by DSCR1, together with another chromosome 21 gene Dyrk1a, may be sufficient to markedly diminish angiogenesis. These data provide a mechanism for the reduced cancer incidence in Down’s syndrome and identify the calcineurin signalling pathway, and its regulators DSCR1 and DYRK1A, as potential therapeutic targets in cancers arising in all individuals.

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Figure 1: Dscr1 expression is upregulated and tumour angiogenesis is suppressed in Down’s syndrome tissues and models.
Figure 2: Targeted Dscr1 transgenic mice with three copies of Dscr1 show inhibition of tumour growth.
Figure 3: Trisomic expression of Dscr1 is necessary for significant suppression of tumour growth in the Ts65Dn Down’s syndrome mouse model.
Figure 4: Calcineurin suppression by DSCR1 and DYRK1A attenuates endothelial cell activation.

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Acknowledgements

We thank G. Evan, C. Kim, K. Cichowski and J. Italiano for critical discussions and advice. This work was supported by the Howard Hughes Medical Institute (G.Q.D.), Harvard Stem Cell Institute (G.Q.D.), the National Institute of Health Director’s Pioneer Award (G.Q.D.), NHLBI (W.C.A.), Jerome Lejeune Foundation (Z.G.), USUHS (Z.G.), the Smith Family Medical Foundation (S.R.), the Garrett B. Smith Foundation (S.R.) and Annie’s Fun Foundation (S.R.).

Author Contributions K.-H.B., A.Z., R.C.L. and C.B. performed the experiments, analysed the data and generated the figures. I.-H.P. and M.W.L. performed experiments. Y.O., R.J.S., T.M., W.C.A. and Z.G. generated the transgenic mouse models in this manuscript and analysed data. G.Q.D. designed experiments and analysed data. S.S.Y. and J.R.K. contributed to pilot experiments. J.F. and S.R. generated the hypotheses. S.R. designed and performed experiments, analysed the data and wrote the manuscript.

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Correspondence to Sandra Ryeom.

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Baek, KH., Zaslavsky, A., Lynch, R. et al. Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1. Nature 459, 1126–1130 (2009). https://doi.org/10.1038/nature08062

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