Sipa1 is a candidate for underlying the metastasis efficiency modifier locus Mtes1

被引:132
作者
Park, YG
Zhao, XH
Lesueur, F
Lowy, DR
Lancaster, M
Pharoah, P
Qian, XL
Hunter, KW
机构
[1] NCI, Lab Populat Genet, Bethesda, MD 20892 USA
[2] Univ Cambridge, Hutchinson MRC Res Ctr, Dept Oncol, Cambridge CB2 2XZ, England
[3] NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA
关键词
D O I
10.1038/ng1635
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
We previously identified loci in the mouse genome that substantially influence the metastatic efficiency of mammary tumors. Here, we present data supporting the idea that the signal transduction molecule, Sipa1, is a candidate for underlying the metastasis efficiency modifier locus Mtes1. Analysis of candidate genes identified a nonsynonymous amino acid polymorphism in Sipa1 that affects the Sipa1 Rap-GAP function. Spontaneous metastasis assays using cells ectopically expressing Sipa1 or cells with knocked-down Sipa1 expression showed that metastatic capacity was correlated with cellular Sipa1 levels. We examined human expression data and found that they were consistent with the idea that Sipa1 concentration has a role in metastasis. Taken together, these data suggest that the Sipa1 polymorphism is one of the genetic polymorphisms underlying the Mtes1 locus. This report is also the first demonstration, to our knowledge, of a constitutional genetic polymorphism affecting tumor metastasis.
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页码:1055 / 1062
页数:8
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