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Tgfbr1 Haploinsufficiency Is a Potent Modifier of Colorectal Cancer Development

¹ Division of Hematology/Oncology, Department of Medicine and Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama; ² Cancer Genetics Program, Division of Hematology/Oncology, Department of Medicine; ³ Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine; ⁴ Department of Pathology; and ⁵ Department of Preventive Medicine, Northwestern University, Chicago, Illinois; ⁶ Human Cancer Genetics Program, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio; and ⁷ Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York

Requests for reprints: Boris Pasche, Division of Hematology/Oncology, Department of Medicine and UAB Comprehensive Cancer Center, The University of Alabama at Birmingham, 1802 6th Avenue South, NP 2566, Birmingham, AL 35294-3300. Phone: 205-934-9591; Fax: 205-996-5975; E-mail: Boris.Pasche{at}ccc.uab.edu.

Key Words: Tgfbr1 • Transforming growth factor beta • haploinsufficiency • colon cancer • SMAD

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^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-β 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-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. [Cancer Res 2009;69(2):678–86]

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