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

Abstract

Individuals with Down's syndrome are known to have a lower rate of certain solid cancers. New work from Baek et al. shows that a mouse model with an extra copy of the chromosome 21 gene Dscr1 (encoding Down syndrome critical region protein 1) exhibits decreased tumour growth due to reduced angiogenesis. They provide evidence that together with another chromosome 21 gene, Dyrk1a, a modest increase in Dscr1 expression limits angiogenesis by decreasing the activity of the calcineurin pathway. 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. Individuals with Down's syndrome are known to have a lower rate of certain solid cancers. Now, a mouse model with one extra copy of Dscr1, a gene located on chromosome 21, is shown to display decreased tumour growth; this is thought to be via suppression of angiogenesis mediated by decreasing the activity of the calcineurin pathway. 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.