Abstract B28: Trisomy suppress tumorgenesis in the NP-cis tumor model

Abstract

Abstract Down syndrome results from trisomy for human chromosome 21 (chr21). People with DS have an increased risk of getting leukemia, but the likelihood of solid tumors might be reduced by contribution of several genes. We showed that trisomy in Ts65Dn “Down syndrome” mice reduces tumor number in the ApcMin model of intestinal cancer and that tumor number is inversely proportional to copy number of the Ets2 gene [Sussan TE, Nature 451, 73–75]. The current study provides evidence for additional dosage sensitive tumor repressor gene(s) in the cancer model, NP-cis. These mice carry a single copy of both the tightly linked Nf1 and p53 genes in cis. Tumors form by LOH. When NP-cis mice were crossed with Ts65Dn, trisomic offspring survived significantly longer than euploid. In contrast to the intestinal adenoma finding, introduction of a null allele of Ets2 in either trisomic or euploid mice (resulting in 2 or one copies of Ets2, respectively) had no effect on survival. This result demonstrates further dosage effects of genes trisomic in these mice and in Down syndrome. The lack of Ets2 effect in the NP-cis model is consistent with a protective mechanism that involves up-regulation of p53 by Ets2, thereby sensitizing trisomic cells to p53-mediated apoptosis. This mechanism would not work in NP-cis since tumors form due to loss of p53. In this regard, in vitro analysis of fibroblast cell lines from several genotypes showed that trisomic cells expressing more Ets2 than euploid were more sensitive to induction of apoptosis by camptothecin and showed a higher frequency of senescence. Other genes, like Endostatin, a cleavage product of Col18a1, and Rcan1 have been shown to inhibit angiogenesis in adosage dependent manner in xenograft models of tumor growth [Zorick TS, EJHG 9, 811-4, Baek KH, Nature 459, 1126-30]. In contrast to results from xenografted tumors, endogenous tumors formed in trisomic, NP-cis mice showed no reduction in angiogenesis. Our findings indicate that multiple mechanisms involving other genes trisomic in Ts65Dn mice likely contribute to reduced tumor incidence in Down syndrome. Citation Information: Cancer Res 2009;69(23 Suppl):B28.