The long term objectives of this proposal are to advance our understanding of the role of somatostatin gene expression in pituitary pathogenesis and in the regulation of pituitary tumor hormone hypersecretion. Because somatostatin is a potent antiproliferative agent in human tumors, the genes for somatostatin receptors which mediate its effects are hypothesized to be tumor suppressor genes. The overall goals of this proposal are: 1) to demonstrate that there are differential and pituitary tumor-specific expression of somatostatin receptor subtypes among human pituitary tumors of different phenotypes; 2) to demonstrate that the efficacy of the somatostatin analogue Octreotide to decrease growth hormone secretion and tumor size in patients with pituitary tumors is dependent upon and can be predicted by the expression of specific somatostatin receptor subtype genes; and 3) to obtain genetic evidence that somatostatin receptor subtype genes function as tumor suppressor genes in human pituitary tumors, and that pituitary tumors exhibit allelic loss and/or mutations in somatostatin receptor subtype genes. Identification of a mutant somatostatin receptor subtype gene in pituitary tumors would be the first example of a mutation in an inhibitory G-protein-linked receptor, and may provide a new pharmacological target for therapeutic intervention for patients with pituitary tumors.
