Familial isolated pituitary adenoma is independent of Ahr genotype in a novel mouse model of disease

Human familial isolated pituitary adenoma (FIPA) has been linked to germline heterozygous mutations in the gene encoding the aryl hydrocarbon receptor-interacting protein (AIP, also known as ARA9, XAP2, FKBP16, or FKBP37). To investigate the hypothesis that AIP is a pituitary adenoma tumor suppressor via its role in aryl hydrocarbon receptor (AHR) signaling, we have compared the pituitary phenotype of our global null Aip (AipΔC) mouse model with that of a conditional null Aip model (Aipfx/fx) carrying the same deletion, as well as pituitary phenotypes of Ahr global null and Arnt conditional null animals. We demonstrate that germline AipΔC heterozygosity results in a high incidence of pituitary tumors in both sexes, primarily somatotropinomas, at 16 months of age. Biallelic deletion of Aip in Pit-1 cells (Aipfx/fx:rGHRHRcre) increased pituitary tumor incidence and also accelerated tumor progression, supporting a loss-of-function/loss-of-heterozygosity model of tumorigenesis. Tumor development exhibited sexual dimorphism in wildtype and Aipfx/fx:rGHRHRcre animals. Despite the role of AHR as a tumor suppressor in other cancers, the observation that animals lacking AHR in all tissues, or ARNT in Pit-1 cells, do not develop somatotropinomas argues against the hypothesis that pituitary tumorigenesis in AIP-associated FIPA is related to decreased activities of either the Ahr or Arnt gene products.