title: Tgfbr1 haploinsufficiency is a potent modifier of colorectal cancer development.
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.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama 35294-3300, USA.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Zeng
authors.forename: Sharbani
authors.initials: S
authors.lastname: Phukan
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Xu
authors.forename: Maureen
authors.initials: M
authors.lastname: Sadim
authors.forename: Diana S
authors.initials: DS
authors.lastname: Rosman
authors.forename: Michael
authors.initials: M
authors.lastname: Pennison
authors.forename: Jie
authors.initials: J
authors.lastname: Liao
authors.forename: Guang-Yu
authors.initials: GY
authors.lastname: Yang
authors.forename: Chiang-Ching
authors.initials: CC
authors.lastname: Huang
authors.forename: Laura
authors.initials: L
authors.lastname: Valle
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Cristofano
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
authors.forename: Boris
authors.initials: B
authors.lastname: Pasche
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006410:Hematopoiesis; D007178:Inbreeding; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse