1. Vascular Biology Program, Department of Surgery, Children's Hospital Boston, Massachusetts 02115, USA
2. Center for Vascular Biology Research, Division of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA
3. Department of Anatomy, Physiology and Genetic, Neuroscience, Molecular and Cellular Biology Program, School of Medicine, Uniformed Services University of the Health Services, Bethesda, Maryland 20814, USA
4. Department of Medicine, Division of Pediatric Hematology Oncology, Children's Hospital Boston, and Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA
5. Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Boston, Maryland 02114, USA
6. Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, 153-8904, Japan
7. Department of Pediatrics and The Brain Institute, The University of Utah, Salt Lake City, Utah 84108, USA
8. These authors contributed equally to this work.

Correspondence to: Sandra Ryeom¹ Correspondence and requests for materials should be addressed to S.R. (Email: sandra.ryeom@childrens.harvard.edu).

Abstract

The incidence of many cancer types is significantly reduced in individuals with Down's syndrome^{1, 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 pathway^{5, 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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