Tgfbr1 Haploinsufficiency is a Potent Modifier of Colorectal Cancer Development

Overview

Journal Cancer Res

Specialty Oncology

Date 2009 Jan 17

PMID 19147584

Citations 32

Authors

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

Affiliations

Soon will be listed here.

Abstract

Transforming growth factor-beta (TGF-beta) signaling is frequently altered in colorectal cancer. Using a novel model of mice heterozygous for a targeted null mutation of Tgfbr1 crossed with Apc(Min/+) mice, we show that Apc(Min/+);Tgfbr1(+/-) mice develop twice as many intestinal tumors as Apc(Min/+);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 Apc(Min/+); Tgfbr1(+/-) mice. Smad-mediated TGF-beta signaling is preserved in both Apc(Min/+);Tgfbr1(+/+) and Apc(Min/+);Tgfbr1(+/-) intestinal tumors, but cyclin D1 expression and cellular proliferation are significantly higher in Apc(Min/+);Tgfbr1(+/-) tumors. These results show that constitutively reduced Tgfbr1-mediated TGF-beta 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.

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