Tgfbr1 haploinsufficiency is a potent modifier of colorectal cancer development

Qinghua Zeng, Sharbani Phukan, Yanfei Xu, Maureen Sadim, Diana S. Rosman, Michael Pennison, Jie Liao, Guang Yu Yang, Chiang Ching Huang, Laura Valle, Antonio Di Cristofano, Albert De La Chapelle, Boris Pasche

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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 ApcMin/+ mice, we show that ApcMin/+;Tgfbr1+/- mice develop twice as many intestinal tumors as ApcMin/+;Tgfbr1+/+ 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 ApcMin/+; Tgfbr 1+/- mice. Smad-mediated TGF-β signaling is preserved in both ApcMin/+;Tgfbr1+/+ and ApcMin/+;Tgfbr1 +/- intestinal tumors, but cyclin D1 expression and cellular proliferation are significantly higher in ApcMin/+;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.

Original languageEnglish (US)
Pages (from-to)678-686
Number of pages9
JournalCancer Research
Volume69
Issue number2
DOIs
StatePublished - Jan 15 2009

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Zeng, Q., Phukan, S., Xu, Y., Sadim, M., Rosman, D. S., Pennison, M., Liao, J., Yang, G. Y., Huang, C. C., Valle, L., Di Cristofano, A., De La Chapelle, A., & Pasche, B. (2009). Tgfbr1 haploinsufficiency is a potent modifier of colorectal cancer development. Cancer Research, 69(2), 678-686. https://doi.org/10.1158/0008-5472.CAN-08-3980