MECHANISMS FOR PITUITARY TUMORIGENESIS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Although pituitary tumors are common monoclonal neoplasms, they rarely metastasize outside the pituitary fossa, but cause considerable morbidity and mortality. Many molecular events underlying pituitary tumorigenesis have been elucidated in recent years, but no clear tumor marker has emerged which assists clinical decisions regarding appropriate therapy. We have recently described a novel estrogen-regulated activating oncogene, Pituitary Tumor Transforming Gene (PTTG), which is potently transforming in vitro and in vivo, regulates basic fibroblast growth factor (bFGF) secretion and inhibits chromatid separation. In experimental animal pituitary tumor models, increased PTTG expression occurs early in cell transformation (normal ? hyperplastic cell) and PTTG overexpression was observed in 99% of pituitary tumors. PTTG presents an attractive target for designing subcellular pituitary tumor therapy and increased understanding of its role and that of other genetic events in pituitary tumorigenesis may provide novel approaches to pituitary tumor management. A novel pituitary tumor transforming gene (PTTG) was previously cloned in our Lab. Normal pituitary had low levels of PTTG, and most pituitary tumor samples expressed higher levels of PTTG. (Zhang X, Horwitz GA, Heanay AP, Nakashima M, Prezant TR, Bronstein MD, and Melmed S. Pituitary tumor transforming gene (PTTG) expression in pituitary adenomas. J Clin Endocrinol Metab 1999, 84: 761-7 ; Prezant TR, Kadioglu P, Melmed S. An intronless homolog of human proto-oncogene hPTTG is expressed in pituitary tumors: evidence for PTTG family. J Clin Endocrinol Metab 1999 84:1149-52) Moreover, PTTG-binding factor, fibroblast growth factor (FGF), and vascular endothelial growth factor (VEGF) were elevated in pituitary tumors, and mostly correlated with PTTG levels. PTTG was induced by estrogen and FGF, and antiestrogen treating human pituitary tumor culture reduced PTTG expression approximately 65%, indicating a role for selective antiestrogens in treating pituitary tumor. (Heaney AP, Fernando M, Melmed S. Functional role of estrogen in pituitary tumor pathogenesis. J Clin Invest. 2002, 109(2): 277-283) PTTG overexpression transgenic mice showed a phenotype switch in early pituitary stem cells and associated with increased tumor invasiveness (Abbud RA, Takumi I, Barker EM, Ren SG, Chen DY, Wawrowsky K, Melmed S. Early multipotential pituitary focal hyperplasia in the alpha-subunit of glycoprotein hormone-driven pituitary tumor-transforming gene transgenic mice. Mol Endocrinol, 2005, 19: 1383-91). PTTG overexpression disrupted mitosis and caused aneuploidy in single live cell (Yu R, Heaney AP, Lu W, Chen J, Melmed S. Pituitary tumor transforming gene causes aneuploidy and p53-dependent and p-53-independent apoptosis. J Biol Chem 2000, 24:36502-5) PTTG silence exhibited a variety of cell growth abnormalities which was associated with induction of p21. ( Chesnokova V, Kovacs K, Castro AV, Zonis S, Melmed S. Pituitary hypoplasia in pttg-/- mice is protective for Rb+/- pituitary tumorigenesis. Mol Endocrinol 2005 19:2371-9 ; Yu R, Melmed S. Pituitary tumor transforming gene: an update. Front Horm Res. 2004, 32: 175-85 ; Wang Z, Yu R, Melmed S. Mice lacking pituitary tumor transforming gene show testicular and splenic hypoplasia, thymic pyperplasia, thrombocytoprnia, aberrant cell cycle progression, and premature centromere division. Mol Endocrinol 2001 15:1870-9) All these observed in mice and cell line will be tested in human pituitary tumor samples using gene transfer or silence techniques. Meanwhile, the effects of somatostatin agonists and antagonists on pituitary hormone secretion and cell proliferation were tested in human pituitary tumor cultures (Anat Ben-Shlomo, Kolja A. Wawrowsky, Irina Proekt et al. Somatostatin receptor type 5 modulates somatostatin receptor type 2 regulation of adrenocorticotropin secretion. J Bio Chem 2005 280: 24011-21; Murray RD, Kim K, Ren SG et al. The novel somatostatin ligand (SOM230) regulates human and rat anterior pituitary hormone secretion. J Clin Endocrinol Matab 2004 89:3027-32; Ren SG, Kim S, Taylor J et al. Suppression of rat and human growth hormone and prolactin secretion by a novel somatostatin/dopaminergic chimeric ligand. J Clin Endocrinol Matab 2003 88:5414-21; Ren SG, Taylor J, Dong J et al. Functional association of somatostatin receptor subtypes 2 and 5 in inhibiting human growth hormone secretion. J Clin Endocrinol Matab 2003 88:4239-45) We will continue the study using human pituitary tumor samples.