title: The Lsktm1 locus modulates lung and skin tumorigenesis in the mouse.
abstract: Alleles derived from skin tumor-resistant Car-R mice provide resistance to both skin and lung tumorigenesis over the susceptibility of the SWR/J strain. In an effort to map tumor modifier loci affecting both tumor types, we carried out a genetic linkage analysis in backcross SWR/J x (SWR/J x Car-R) mice and identified a locus (Lsktm1) on chromosome 1 linked to both skin (LOD score = 3.93) and lung (LOD score = 8.74) tumorigenesis. Two genes, Igfbp5 and Igfbp2, residing in this locus and belonging to the insulin-like growth factor binding protein family were expressed at significantly greater levels in normal lung tissue from cancer-resistant Car-R mice than in cancer-susceptible SWR/J mice. Overexpression of the recombinant Igfbp5 and Igfbp2 genes in two lung cancer cell lines significantly inhibited clonogenicity (P < 0.0001). Collectively, we have identified a single polymorphic locus that affects skin and lung tumorigenesis and identify Igfbp5 and Igfbp2 as candidate modifier genes of lung tumorigenesis.
authors.affiliation: Department of Predictive and Preventive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Galvan
authors.forename: Francesca
authors.initials: F
authors.lastname: Colombo
authors.forename: Sara
authors.initials: S
authors.lastname: Noci
authors.forename: Simonetta
authors.initials: S
authors.lastname: Pazzaglia
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Mancuso
authors.forename: Giacomo
authors.initials: G
authors.lastname: Manenti
authors.forename: Karl W
authors.initials: KW
authors.lastname: Broman
authors.forename: Anna
authors.initials: A
authors.lastname: Saran
authors.forename: Tommaso A
authors.initials: TA
authors.lastname: Dragani
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian; D005260:Female; D015870:Gene Expression; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics*; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D051379:Mice; D020641:Polymorphism, Single Nucleotide; D018179:Receptors, Thrombin / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics*; D014410:Tumor Stem Cell Assay
chemical_list: D018971:Insulin-Like Growth Factor Binding Protein 2; D018975:Insulin-Like Growth Factor Binding Protein 5; D018179:Receptors, Thrombin; C112908:protease-activated receptor 4