The Lsktm1 locus modulates lung and skin tumorigenesis in the mouse

G3 (Bethesda). 2012 Sep;2(9):1041-6. doi: 10.1534/g3.112.003525. Epub 2012 Sep 1.

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.

Keywords: cancer modifier genes; disease models; lung cancer; quantitative trait loci (QTLs); single-nucleotide polymorphisms; skin cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics*
  • Chromosome Mapping
  • Chromosomes, Mammalian
  • Female
  • Gene Expression
  • Genetic Loci*
  • Genome-Wide Association Study
  • Humans
  • Insulin-Like Growth Factor Binding Protein 2 / genetics*
  • Insulin-Like Growth Factor Binding Protein 5 / genetics*
  • Lung Neoplasms / genetics*
  • Male
  • Mice
  • Polymorphism, Single Nucleotide
  • Receptors, Thrombin / genetics
  • Skin Neoplasms / genetics*
  • Tumor Stem Cell Assay

Substances

  • Insulin-Like Growth Factor Binding Protein 2
  • Insulin-Like Growth Factor Binding Protein 5
  • Receptors, Thrombin
  • protease-activated receptor 4