Publications

Abstract

Activation of embryonic signaling pathways quiescent in the adult pancreas is a feature of pancreatic cancer. These discoveries have led to the development of novel inhibitors of pathways such as Notch and Hedgehog signaling that are currently in early phase clinical trials. Retinoid signaling is also essential for pancreatic development, and retinoid therapy is used successfully in other malignancies such as leukemia, but little is known concerning retinoid signaling in pancreatic cancer. We investigated retinoid signaling in normal pancreas, pancreatic regeneration and cancer. Retinoid signaling is active in occasional cells in the adult pancreas but is markedly augmented throughout the parenchyma during regeneration. Both chemically induced and genetically engineered mouse models of pancreatic cancer exhibit a lack of retinoid signaling activity compared to normal pancreas. As a consequence, we investigated Cellular Retinoid Binding Protein 1 (CRBP1), known to play a role in breast cancer development and a key regulator of retinoid signaling, for its role in pancreatic carcinogenesis and its potential as a therapeutic target. Loss, or significant downregulation of CRBP1 was present in 70% of human pancreatic cancer, and was evident in the very earliest precursor lesions (PanIN-1A). However, in vitro gain and loss of function studies and CRBP1 knockout mice suggested that loss of CRBP1 expression alone was not sufficient to induce carcinogenesis or to alter pancreatic cancer sensitivity to retinoid based therapies. In conclusion, retinoid signaling appears to play a role in pancreatic regeneration and carcinogenesis, but unlike breast cancer, it is not mediated directly by CRBP1.