A murine model supports the role of PRKAR1A as a tumor suppressor gene in the pancreas.

Wednesday, October 10, 2012 — Poster Session II
Noon – 2:00 p.m	Natcher Conference Center, Building 45	NICHD	CANCER-27

Authors

• E. Saloustros
• M Nesterova
• O Gavrilova
• A Moraitis
• S Liu
• M Hussain
• C Stratakis

Abstract

Background: Carney complex is a rare disease caused by inactivation of PRKAR1A. Recently a possible association of pancreatic neoplasms with CNC was reported in 9/354 patients. A mouse model with tissue specific prkar1a ablation is likely to elucidate insights on the role of prkar1a in pancreatic tumorigenesis. Methods: Prkar1afl/fl and Pdx-1-CRE mice were previously reported. Pdx1 is expressed in beta-insulin producing and in some a-glucagon producing cells of the islets. Both prkar1a alleles were conditionally deleted during development by generating Pdx1-Cre; prkar1af/f mice. Results: Mice developed invasive carcinomas with 100% penetration by the age of 4-5 months. The lesions resemble normal-looking islet cells arranged in cords or trabeculae of cells with bland round to oval nuclei with small nucleoli and modest amounts of cytoplasm. Malignancy defined by local invasion. A mixed cell population of beta (mostly) and alpha cells composed the tumors. Since fasting (18h) revealed decrease in glucose levels in Δ–prkar1a mice the probability that these tumors are functional is high. Conclusions: Loss of prkar1a function predisposes pancreas to invasive islet cell carcinomas. This supports the role of prkar1a as tumor suppressor gene in the pancreas and provides valuable tools to evaluate novel therapeutics in pancreatic malignancies.

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