Abstract 3144:Tgfbr1haploinsufficiency inhibits the development of murine mutantKras-induced pancreatic precancer

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Abstract Transforming Growth Factor Beta (TGFβ) signaling can play dual roles in pancreatic tumor development. In human pancreatic cancer, loss of DPC4/smad4 has been observed in more than half of all pancreatic cancers. In vivo loss of either Smad4 or Tgfbr2 promotes pancreatic adenocarcinoma in mice expressing mutant Kras. Conversely, pharmacologically-induced reduction in Tgfbr1 kinase activity attenuates growth and metastasis of Panc1 cells orthotopically injected into mouse pancreas. To dissect the role of constitutively altered Tgfbr1 signaling in pancreatic cancer development, we crossed Elastase-KrasG12D (EL-Kras) mice with Tgfbr1 haploinsufficient mice to generate EL-Kras/Tgfbr1+/− mice. Mice were euthanized at 6-9 months to compare the incidence, frequency, and size of precancerous lesions in the pancreas. Only 50% of all EL-Kras/Tgfbr1+/− mice developed preinvasive lesions compared to 100% of EL-Kras (wild type Tgfbr1) mice. The frequency of precancerous lesions was 4-fold lower in haploinsufficient than in control mice. The mitotic index of precancerous cells and the observable levels of fibrosis, lipoatrophy, and lymphocytic infiltration were reduced in EL-Kras/Tgfbr1+/− mice. Tgfbr1 haploinsufficiency was demonstrated by decreased levels of psmad2, psmad3, and nuclear localization of psmad4 and was culminated by a reduction in the Tgfbr1: Tgfbr2 ratio in whole mouse pancreas, which was predominantly caused by increased Tgfbr2. Paradoxically, the precancerous lesions of EL-Kras/Tgfbr1+/− mice were considerably larger than those in EL-Kras mice, which was due, in part, to a reduced level of apoptosis. We conclude that Tgfbr1 signaling promotes the development of precancerous lesions in mice. These findings correlate with TGF-β signals that increase ECM deposition and augment immune responses and strongly suggest that Tgfbr1 haploinsufficiency may have a protective role with respect to early pancreatic cancer development. It is also possible that individuals with constitutively decreased TGFBR1 expression may have a decreased risk of pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3144.