Tgfbr1 haploinsufficiency is a potent modifier of colorectal cancer development.
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.
Zeng
Qinghua
Q
Department of Medicine, Division of Hematology/Oncology, Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama 35294-3300, USA.
Phukan
Sharbani
S
Xu
Yanfei
Y
Sadim
Maureen
M
Rosman
Diana S
DS
Pennison
Michael
M
Liao
Jie
J
Yang
Guang-Yu
GY
Huang
Chiang-Ching
CC
Valle
Laura
L
Di Cristofano
Antonio
A
de la Chapelle
Albert
A
Pasche
Boris
B
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
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