RGD Reference Report - Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-beta signaling in cooperation with active Kras expression.

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Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-beta signaling in cooperation with active Kras expression.
Authors:	Ijichi, H Chytil, A Gorska, AE Aakre, ME Fujitani, Y Fujitani, S Wright, CV Moses, HL
Citation:	Ijichi H, etal., Genes Dev. 2006 Nov 15;20(22):3147-60.
RGD ID:	2317498
Pubmed:	PMID:17114585 (View Abstract at PubMed)
PMCID:	PMC1635149 (View Article at PubMed Central)
DOI:	DOI:10.1101/gad.1475506 (Journal Full-text)
Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease in humans. Transforming growth factor-beta (TGF-beta) signaling plays an important role in PDAC progression, as indicated by the fact that Smad4, which encodes a central signal mediator downstream from TGF-beta, is deleted or mutated in 55% and the type II TGF-beta receptor (Tgfbr2) gene is altered in a smaller subset of human PDAC. Pancreas-specific Tgfbr2 knockout mice have been generated, alone or in the context of active Kras (Kras(G12D)) expression, using the Cre-loxP system driven by the endogenous Ptf1a (pancreatic transcription factor-1a) locus. Pancreas-selective Tgfbr2 knockout alone gave no discernable phenotype in 1.5 yr. Pancreas-specific Kras(G12D) activation alone essentially generated only intraepithelial neoplasia within 1 yr. In contrast, the Tgfbr2 knockout combined with Kras(G12D) expression developed well-differentiated PDAC with 100% penetrance and a median survival of 59 d. Heterozygous deletion of Tgfbr2 with Kras(G12D) expression also developed PDAC, which indicated a haploinsufficiency of TGF-beta signaling in this genetic context. The clinical and histopathological manifestations of the combined Kras(G12D) expression and Tgfbr2 knockout mice recapitulated human PDAC. The data show that blockade of TGF-beta signaling and activated Ras signaling cooperate to promote PDAC progression.

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
TGFBR2	Human	pancreatic ductal carcinoma		ISO	Tgfbr2 (Mus musculus)		RGD
Tgfbr2	Rat	pancreatic ductal carcinoma		ISO	Tgfbr2 (Mus musculus)		RGD
Tgfbr2	Mouse	pancreatic ductal carcinoma		IMP			RGD

Objects Annotated

Genes (Rattus norvegicus)

Tgfbr2 (transforming growth factor, beta receptor 2)

Genes (Mus musculus)

Tgfbr2 (transforming growth factor, beta receptor II)

Genes (Homo sapiens)

TGFBR2 (transforming growth factor beta receptor 2)

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Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-beta signaling in cooperation with active Kras expression.