title: Sipa1 is a candidate for underlying the metastasis efficiency modifier locus Mtes1.
abstract: 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.
authors.affiliation: Laboratory of Population Genetics, National Cancer Institute, Building 41, Room 702, 41 Library Drive, Bethesda, Maryland 20892, USA.
authors.forename: Yeong-Gwan
authors.initials: YG
authors.lastname: Park
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhao
authors.forename: Fabienne
authors.initials: F
authors.lastname: Lesueur
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Lowy
authors.forename: Mindy
authors.initials: M
authors.lastname: Lancaster
authors.forename: Paul
authors.initials: P
authors.lastname: Pharoah
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Qian
authors.forename: Kent W
authors.initials: KW
authors.lastname: Hunter
mesh_terms: D000818:Animals; D001681:Biological Assay; D019556:COS Cells; D002448:Cell Adhesion / Q000235:genetics; D002522:Chlorocebus aethiops; D020690:GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D009154:Mutation; D009362:Neoplasm Metastasis / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D015533:Transcriptional Activation; D020668:rap GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C490403:SIPA1 protein, human; C091108:Sipa1 protein, mouse; D020668:rap GTP-Binding Proteins