Tgfbr1 haploinsufficiency is a potent modifier of colorectal cancer development

Academic Article

Abstract

  • Transforming growth factor-β (TGF-β) signaling is frequently altered in colorectal cancer. Using a novel model of mice heterozygous for a targeted null mutation of Tgfbr1 crossed with Apc mice, we show that Apc ;Tgfbr mice develop twice as many intestinal tumors as Apc ;Tgfbr mice, as well as adenocarcinoma of the colon, without loss of heterozygosity at the Tgfbr1 locus. Decreased Smad2 and Smad3 phosphorylation and increased cellular proliferation are observed in the colonic epithelium crypts of Apc ; Tgfbr mice. Smad-mediated TGF-β signaling is preserved in both Apc ;Tgfbr1 and Apc ;Tgfbr1 intestinal tumors, but cyclin D1 expression and cellular proliferation are significantly higher in Apc ;Tgfbr1 tumors. These results show that constitutively reduced Tgfbr1-mediated TGF-β signaling significantly enhances colorectal cancer development and results in increased tumor cell proliferation. These findings provide a plausible molecular mechanism for colorectal cancer development in individuals with constitutively altered TGFBR1 expression, a recently identified common form of human colorectal cancer. ©2009 American Association for Cancer Research. Min/+ Min/+ 1+/- Min/+ 1+/+ Min/+ 1+/- Min/+ +/+ Min/+ +/- Min/+ +/-
  • Published In

  • Cancer Research  Journal
  • Digital Object Identifier (doi)

    Author List

  • Zeng Q; Phukan S; Xu Y; Sadim M; Rosman DS; Pennison M; Liao J; Yang GY; Huang CC; Valle L
  • Start Page

  • 678
  • End Page

  • 686
  • Volume

  • 69
  • Issue

  • 2