MECHANISMS FOR PITUITARY TUMORIGENESIS

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Pituitary adenomas are common benign neoplasms giving rise to disorders of growth, reproductive function, cortisol production and local central pressure effects. Although recently determined to be monoclonal, the genetic mechanisms involved in pituitary cell transformation are unclear. This proposal will characterize the transforming properties of PTTG, a novel pituitary tumor derived protein. We used differential RNA display to identify a rat pituitary derived transforming gene (PTTG) which encodes a 199 a.a. novel protein. Now, we will isolate and study human PTTG and assign its chromosomal locus. PTTG expression will be tested in hormone- secreting (PRL, GH, ACTH) and non-functional pituitary tumors, and its abundance assessed as a function of pituitary adenoma grading, invasinenes, hormonal activity and ultimately long-term clinical outcome. Cellular localization of PTTG will also be determined in these tumors by double immunostaining and in situ techniques. Models of pituitary enlargement (pregnancy and estrogen-induced prolactinomas) will be used to determine PTTG expression in the pathogenesis of the pituicyte to hyperplasia to adenoma formation. PTTG in vitro and in vivo transforming properties will be determined in double agar transformation assays, nude mouse tumorigenesis and growth factor regulation will be assessed. Effects of inducible PTTG expression on cell proliferation will also be assessed. These studies will thus provide mechanistic insight into the pathogenesis of prolactinomas, acromegaly, Cushing's Disease and non-secreting pituitary tumors.