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Molecular Basis of Pituitary Oncogenesis

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Abstract

Recent advances in the molecular biology has served to unveil the underlying genetic and epigenetic alterations in pituitary adenomas. Three nuclear transcriptional factors, AP-1, CREB, and Pit-1, which are targets of protein kinase C and A, appear to play critical roles in both neoplastic growth and hormone secretion in hormone-producing adenomas. The alteration of G proteins such as Gs α and Gi2 α is a direct cause of the activation of such transcriptional factors. Autocrine growth factor/cytokine loops also contribute to the augmented signal transductions. Bromocriptine and somatostatin analogs have effects to lower cellular cAMP level through inhibitory G proteins, although the mechanism leading to cellular apoptosis is unknown. On the other hand, most non-functioning adenomas may not have PKC- or PKA-mediated oncogenic mechanisms. Although the loss of Rb and p27Kip1 genes has been demonstrated as a cause of murine pituitary adenomas, the role of tumor suppressor genes for human pituitary adenomas remains elusive. However, potential candidates for the suppressor genes are now emerging. The recently cloned multiple endocrine neoplasia type I gene is one example. Alterations of c-myc/bcl-2, and ras, although rare, appear to be an important cause of the process by which adenoma cells aquire aggressive phenotypes. Further studies on the links between abnormal signal transductions and aberrant tumor suppressor genes will be needed to clarify the whole picture of pituitary oncogenesis.

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References

  1. The Committee of the Brain Tumor Registry in Japan Brain Tumor Registry of Japan. 1996 edition, 1996

  2. CBTRUS 1996 Annual Report: Central Brain Tumor Registry of the United States, 1997

  3. Costello RT: Subclinical adenoma of the pituitary gland. Am J pathol 12: 205–215, 1936

    Google Scholar 

  4. McComb DJ, Ryan N, Horvath E, Kovacs K: Subclinical adenomas of the human pituitary. New light on old problems. Arch Pathol Lab Med 107: 488–491, 1983

    Google Scholar 

  5. Hall WA, Luciano MG, Doppman JL, Patronas NJ, Oldfield EH: Pituitary magnetic resonance imaging in normal human volunteers: occult adenomas in the general population. Ann Intern Med 120: 817–820, 1994

    Google Scholar 

  6. Thapar K, Scheithauer BW, Kovacs K, Pernicone PJ, Laws ERJ: p53 expression in pituitary adenomas and carcinomas: correlation with invasiveness and tumor growth fractions. Neurosurgery 38: 763–770, 1996

    Google Scholar 

  7. Thapar K, Kovacs K, Scheithauer BW, Stefaneanu L, Horvath E, Pernicone PJ, Murray D, Laws ER Jr: Proliferative activity and invasiveness among pituitary adenomas and carcinomas: an analysis using the MIB-1 antibody. Neurosurgery 38: 99–106, 1996

    Google Scholar 

  8. Lee AK, DeLellis RA, Blount M, Nunnemacher G, Wolfe HJ: Pituitary proliferative lesions in aging male Long–Evans rats. A model of mixed multiple endocrine neoplasia syndrome. Lab Invest 47: 595–602, 1982

    Google Scholar 

  9. Kovacs K, Ilse G, Ryan N, McComb DJ, Horvath E, Chen HJ, Walfish PG: Pituitary prolactin cell hyperplasia. Horm Res 12: 87–95, 1980

    Google Scholar 

  10. McComb DJ, Hellmann P, Thorner MO, Scoot D, Evans WS, Kovacs K: Morphologic effects of bromocriptine on spontaneously occurring pituitary prolactin-cell hyperplasia in old Long–Evans rats. AmJ Pathol 122: 7–16, 1986

    Google Scholar 

  11. Chandra M, Riley MG, Johnson DE: Spontaneous neoplasms is aged Sprague–Dawley rats. Arch Toxical 66: 496–502, 1992

    Google Scholar 

  12. Stefaneanu L, Kovacs K, Horvath E, Asa SL, Losinski NE, Billestrup N, Price J, Vale W: Adenohypophysial changes in mice transgenic for human growth hormone-releasing factor: a histological, immunocytochemical, and electron microscopic investigation. Endocrinology 125: 2710–2718, 1989

    Google Scholar 

  13. Burton FH, Hasel KW, Bloom FE, Sutcliffe JG: Pituitary hyperplasia and gigantism in mice caused by a cholera toxin transgene. Nature 350: 74–77, 1991

    Google Scholar 

  14. Bourne HR, Sanders DA, McCormick F: The GTPase superfamily: conserved structure and molecular mechanism. Nature 349: 117–127, 1991

    Google Scholar 

  15. Weinberg RA: Tumor suppressor genes. Science 254: 1138–1146, 1991

    Google Scholar 

  16. Hu N, Gutsmann A, Herbert DC, Bradley A, Lee WH, Lee EY: Heterozygous Rb-1 delta 20/+mice are predisposed to tumors of the pituitary gland with a nearly complete penetrance. Oncogene 9: 1021–1027, 1994

    Google Scholar 

  17. Fero ML, Rivkin M, Tasch M, Porter P, Carow CE, Firpo E, Polyak K, Tsai LH, Broudy V, Perlmutter RM, Kaushansky K, Roberts JM: A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27(Kip1)-deficient mice. Cell 85: 733–744, 1996

    Google Scholar 

  18. Kiyokawa H, Kineman RD, Manova Todorova KO, Soares VC, Hoffman ES, Ono M, Khanam D, Hayday AC, Frohman LA, Koff A: Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27(Kip1). Cell 85: 721–732, 1996

    Google Scholar 

  19. Helseth A, Haug E, Nesland JM, Siegal GP, Fodstad O, Bautch VL: Endocrine and metabolic characteristics of polyoma large T transgenic mice that develop ACTHproducing pituirary tumors. J Neurosurg 82: 879–885, 1995

    Google Scholar 

  20. Freund R, Bronson RT, Benjamin TL: Separation of immortalization from tumor induction with polyoma large T mutants that fail to bind the retinoblastoma gene product. Oncogene 7: 1979–1987, 1992

    Google Scholar 

  21. Stefaneanu L, Rindi G, Horvath E, Murphy D, Polak JM, Kovacs K: Morphology of adenohypophysial tumors in mice transgenic for vasopressin-SV40 hybrid oncogene. Endocrinology 130: 1789–1795, 1992

    Google Scholar 

  22. Alarid ET, Windle JJ, Whyte DB, Mellon PL: Immortalization of pituitary cells at discrete stages of development by directed oncogenesis in transgenic mice. Development 122: 3319–3329, 1996

    Google Scholar 

  23. Maki K, Miyoshi I, Kon Y, Yamashita T, Sasaki N, Aoyama S, Takahashi E, Namioka S, Hayashizaki Y, Kasai N: Targeted pituitary tumorigenesis using the human thyrotropin beta-subunit chain promoter in transgenic mice. Mol Cell Endocrinol 105: 147–154, 1994

    Google Scholar 

  24. Low MJ, Liu B, Hammer GD, Rubinstein M, Allen RG: Post-translational processing of proopiomelanocortin (POMC) in mouse pituitary melanotroph tumors induced by a POMC-simian virus 40 large T antigen transgene. J Biol Chem 268: 24967–24975, 1993

    Google Scholar 

  25. Kovacs K, Horvath E: Pathology of pituitary tumors. Endocrinol Metab Clin North Am 16: 529–551, 1987

    Google Scholar 

  26. Beck Peccoz P, Persani L, Asteria C, Cortelazzi D, Borgato S, Mannavola D, Romoli R: Thyrotropin-secreting pituitary tumors in hyper-and hypothyroidism. Acta Med Austriaca 23: 41–46, 1996

    Google Scholar 

  27. Vallar L, Spada A, Giannattasio G: Altered Gs and adenylate cyclase activity in human GH-secreting pituitary adenomas. Nature 330: 566–568, 1987

    Google Scholar 

  28. McKusick VA: *174800 Polyostotic fibrous dysplasia [PFD; POFD; Albright syndrome; McCune–Albright syndrome; MAS], 11th edn, Vol 1, Baltimore: Johns Hopkins University Press, 1994, pp. 1180–1182

    Google Scholar 

  29. Spada A, Vallar L, Faglia G: G-proteins and hormonal signalling in human pituitary tumors: genetic mutations and functional alterations. Front Neuroendocrinol 14: 214–232, 1993

    Google Scholar 

  30. Adams EF, Lei T, Buchfelder M, Petersen B, Fahlbusch R: Biochemical characteristics of human pituitary somatotropinomas with and without gsp mutations: in vitro cell culture studies. J Clin Endocrinol Metab 80: 2077–2081, 1995

    Google Scholar 

  31. Boothroyd CV, Grimmond SM, Cameron DP, Hayward NK: G protein mutations in tumours of the pituitary, parathyroid and endocrine pancreas. Biochem Biophys Res Commun 211: 1063–1070, 1995

    Google Scholar 

  32. Wilson BS, Komuro M, Farquhar MG: Cellular Variations in heterotrimeric G protein localization and expression in rat pituitary. Endocrinology 134: 233–244, 1994

    Google Scholar 

  33. Williamson EA, Daniels M, Foster S, Kelly WF, Kendall Taylor P, Harris PE: Gs? and Gi2? mutations in clinically non-functioning pituitary tumours. Clin Endocrinol (Oxf) 41: 815–820, 1994

    Google Scholar 

  34. Harris PE: Gs protein mutations and the pathogenesis and function of pituitary tumors. Metabolism 45: 120–122, 1996

    Google Scholar 

  35. Florio T, Perrino BA, Stork PJ: Cyclic 3,5—adenoise monophosphate and cyclosporin A inhibit cellular proliferation and serine/threonine protein phosphatase activity in pituitary cells. Endocrinology 137: 4409–4418, 1996

    Google Scholar 

  36. Bertherat J, Chanson P, Montminy M: The cyclic adenosine 3?;5?-monophosphate-responsive factor CREB is constitutively activated in human somatotroph adenomas. Mol Endocrinol 9: 777–783, 1995

    Google Scholar 

  37. Adams EF, Brockmeier S, Friedmann E, Roth M, Buchfelder M, Fahlbusch R: Clinical and biochemical characteristics of acromegalic patients harboring gsppositive and gsp-negative pituitary tumors. Neurosurgery 33: 198–203, 1993

    Google Scholar 

  38. Faglia G, Arosio M, Spada A: GS protein mutations and pituitary tumors: functional correlates and possible therapeutic implications. Metabolism 45: 117–119, 1996

    Google Scholar 

  39. Clapham DE: Mutations in G protein-linked receptors: novel insights on disease. Cell 75: 1237–1239, 1993

    Google Scholar 

  40. McKusick VA: *139320 Guanine nucleotide-binding protein, alpha-stimulating polypeptide [GNAS; GNAS1; Gs, alpha subunit; stimulatory G protein; adenylate cyclase stimulatory protein, alpha subunit; GSP, included], 11th edn, Vol 1, Baltimore: Johns Hopkins University Press, 1994, pp 605–606

    Google Scholar 

  41. Ringel MD, Schwindinger WF, Levine MA: Clinical implications of genetic defects in G proteins. The molecular basis of McCune–Albright syndrome and Albright hereditary osteodystrophy. Medicine 75: 171–184, 1995

    Google Scholar 

  42. Steinfelder HJ, Radovick S, Wondisford FE: Hormonal regulation of the thyrotropin beta-subunit gene by phosphorylation of the pituitary-specific transcription factor Pit-1. Proc Natl Acad Sci USA 89: 5942–5945, 1992

    Google Scholar 

  43. Asa SL, Puy LA, Lew AM, Sundmark VC, Elsholtz HP: Cell type-specific expression of the pituitary transcription activator pit-1 in the human pituitary and pituitary adenomas. J Clin Endocrinol Metab 77: 1275–1280, 1993

    Google Scholar 

  44. Delhase M, Vergani P, Malur A, Velkeniers B, Teugels E, Trouillas J, Hooghe Peters EL: Pit-1/GHF-1 expression in pituitary adenomas: further analogy between human adenomas and rat SMtTW tumours. J Mol Endocrinol 11: 129–139, 1993

    Google Scholar 

  45. Lloyd RV, Jin L, Chandler WF, Horvath E, Stefaneanu L, Kovacs K: Pituitary specific transcription factor messenger ribonucleic expression in adenomatous and nontumorous human pituitary tissues. Lab Invest 69: 570–575, 1993

    Google Scholar 

  46. Hamada K, Nishi T, Kuratsu J, Ushio Y: Expression and alternative splicing of Pit-1 messenger ribonucleic acid in pituitary adenomas. Neurosurgery 38: 362–366, 1996

    Google Scholar 

  47. Gaiddon C, Tian J, Loeffler JP, Bancroft C: Constitutively active G(S) alpha-subunits stimulate Pit-1 promoter activity via a protein kinase A-mediated pathway acting through deoxyribonucleic acid binding sites both for Pit-1 and for adenosine 3?;5?-monophosphate response element-binding protein. Endocrinology 137: 1286–1291, 1996

    Google Scholar 

  48. Jong MT, Raaka BM, Samuels HH: A sequence in the rat Pit-1 gene promoter confers synergistic activation by glucocorticoids and protein kinase-C. Mol Endocrinol 8: 1320–1327, 1994

    Google Scholar 

  49. Coleman DT, Chen X, Sassaroli M, Bancroft C: Pituitary adenylate cyclase-activating polypeptide regulates prolactin promoter activity via a protein kinase Amediated pathway that is independent of the transcriptional pathway employed by thyrotropin-releasing hormone. Endocrinology 137: 1276–1285, 1996

    Google Scholar 

  50. Kim DS, Yoon JH, Ahn SK, Kim KE, Seong RH, Hong SH, Kim K, Ryu K, Park SD: A 33 kDa Pit-1-like protein binds to the distal region of the human thyrotrophin alpha-subunit gene. J Mol Endocrinol 14: 313–322, 1995

    Google Scholar 

  51. Kraus J, Hollt V: Identification of a cAMP-response element on the human proopiomelanocortin gene upstream promoter. DNA Cell Biol 14: 103–110, 1995

    Google Scholar 

  52. Brent GA, Harney JW, Moore DD, Larsen PR: Multihormonal regulation of the human, rat, and bovine growth hormone promoters: differential effects of 3?;5?-cyclic adenosine monophosphate, thyroid hormone, and glucocorticoids. Mol Endocrinol 2: 792–798, 1988

    Google Scholar 

  53. Rousseau GG: Growth hormone gene regulation by transacting factors. Horm Res 3: 88–92, 1992

    Google Scholar 

  54. Boutillier AL, Monnier D, Lorang D, Lundblad JR, Roberts JL, Loeffler JP: Corticotropin-releasing hormone stimulates proopiomelanocortin transcription by cFosdependent and-independent pathways: characterization of an AP1 site in exon 1. Mol Endocrinol 9: 745–755, 1995

    Google Scholar 

  55. Lamonerie T, Tremblay JJ, Lanctot C, Therrien M, Gauthier Y, Drouin J: Ptx1, a bicoid-related homeo box transcription factor involved in transcription of the proopiomelanocortin gene. Genes Dev 10: 1284–1295, 1996

    Google Scholar 

  56. Kim MK, McClaskey JH, Bodenner DL, Weintraub BD: An AP-1-like factor and the pituitary-specific factor Pit-1 are both necessary to mediate hormonal induction of human thyrotropin beta gene expression. J Biol Chem 268: 23366–23375, 1993

    Google Scholar 

  57. Bradford AP, Conrad KE, Tran PH, Ostrowski MC, Gutierrez-Hartmann A: GHF-1/Pit-1 functions as a cellspecific integrator of Ras Signaling by targeting the Ras pathway to a composite Ets-1/GHF-1 response element. J Biol Chem 271: 24639–24648, 1996

    Google Scholar 

  58. Bradford AP, Wasylyk C, Wasylyk B, Gutierrez-Hartmann A: Interaction of Ets-1 and the POUhomeodomain protein GHF-1/Pit-1 reconstitutes pituitaryspecific gene expression. Mol Cell Biol 17: 1065–1074, 1997

    Google Scholar 

  59. Allen DL, Mitchner NA, Uveges TE, Nephew KP, Khan S, Ben JN: Cell-specific induction of c-fos expression in the pituitary gland by estrogen. Endocrinology 138: 2128–2135, 1997

    Google Scholar 

  60. Cook SJ, McCormick F: Inhibition by cAMP of Rasdependent activation of Raf. Science 262: 1069–1072, 1993

    Google Scholar 

  61. Wu J, Dent P, Jelinek T, Wolfman A, Weber MJ, Sturgill TW: Inhibition of the EGF-activated MAP kinase signaling pathway by adenosine 3?;5?-monophosphate. Science 262: 1065–1069, 1993

    Google Scholar 

  62. Dekker LV, Parker PJ: Protein kinase C – a question of specificity. Trends Biol Sci 19: 73–77, 1994

    Google Scholar 

  63. Levin DE, Fields FO, Kunisawa R, Bishop JM, Thorner J: A candidate protein kinase C gene, PKC1, is required for the S. cerevisiae cell cycle. Cell 62: 213–224, 1990

    Google Scholar 

  64. Yamamoto KK, Gonzalez GA, Biggs WHI, Montminy MR: Phosphorylation-induced binding and transcriptional efficacy of nuclear factor CREB. Nature 334: 494–498, 1988

    Google Scholar 

  65. Gordeladze JO, Sletholt K, Thorn NA, Gautvik KM: Hormone-sensitive adenylate cyclase of prolactinproducing rat pituitary adenoma (GH4C1) cells: molecular organization. Eur J Biochem 177: 665–672, 1988

    Google Scholar 

  66. Alvaro V, Prevostel C, Joubert D, Slosberg E, Weinstein BI: Ectopic expression of a mutant form of PKC alpha originally found in human tumors: aberrant subcellular translocation and effects on growth control. Oncogene 14: 677–685, 1997

    Google Scholar 

  67. Schiemann U, Assert R, Moskopp D, Gellner R, Hengst K, Gullotta F, Domschke W, Pfeiffer A: Analysis of a protein kinase C-alpha mutation in human pituitary tumours. J Endocrinol 153: 131–137, 1997

    Google Scholar 

  68. Couldwell WT, Law RE, Hinton DR, Gopalakrishna R, Yong VW, Weiss MH: Protein kinase C and growth regulation of pituitary adenomas. Acta Neurochir 65 (Suppl) (Wien): 22–26, 1996

    Google Scholar 

  69. Jin L, Maeda T, Chandler WF, Lloyd RV: Protein kinase C (PKC) activity and PKC messenger RNAs in human pituitary adenomas. Am J pathol 142: 569–578, 1993

    Google Scholar 

  70. Hamilton HB, Hinton DR, Law RE, Gopalakrishna R, Su YZ, Chen ZH, Weiss MH, Couldwell WT: Inhibition of cellular growth and induction of apoptosis in pituitary adenoma cell lines by the protein kinase C inhibitor hypericin: potential therapeutic application. J Neurosurg 85: 329–334, 1996

    Google Scholar 

  71. Pellegrini I, Rasolonjanahary R, Gunz G, Bertrand P, Delivet S, Jedynak CP, Kordon C, Peillon F, Jaquet P, Enjalbert A: Resistance to bromocriptine in prolactinomas. J Clin Endocrinol Metab 69: 500–509, 1989

    Google Scholar 

  72. Wood DF, Johnston JM, Johnston DG: Dopamine, the dopamine D2 receptor and pituitary tumours. Clin Endocrinol (Oxf) 35: 455–466, 1991

    Google Scholar 

  73. Caccavelli L, Feron F, Morange I, Rouer E, Benarous R, Dewailly D, Jaquet P, Kordon C, Enjalbert A: Decreased expression of the two D2 dopamine receptor isoforms in bromocriptine-resistant prolactinomas. Neuroendocrinology 60: 314–322, 1994

    Google Scholar 

  74. Lew AM, Yao H, Elsholtz HP: G(i) alpha 2-and G(o) alpha-mediated signaling in the Pit-1-dependent inhibition of the prolactin gene promoter. Control of transcription by dopamine D2 receptors. J Biol Chem 269: 12007–12013, 1994

    Google Scholar 

  75. Senogles SE: The D2 dopamine receptor isoforms signal through distinct Gi alpha proteins to inhibit adenylyl cyclase. A study with site-directed mutant Gi alpha proteins. J Biol Chem 269: 23120–23127, 1994

    Google Scholar 

  76. Chuang TT, lacovelli L, Sallese M, De Blasi A: G proteincoupled receptors: heterologous regulation of homologous desensitization and its implications. Trends pharmacol Sci 17: 416–421, 1996

    Google Scholar 

  77. Barlier A, Pellegrini-Bouiller I, Caccavelli L, Gunz G, Morange-Ramos I, Jaquet P, Enjalbert A: Abnormal transduction mechanisms in pituitary adenomas. Horm Res 47: 227–234, 1997

    Google Scholar 

  78. Caccavelli L, Cussac D, Pellegrini I, Audinot V, Jaquet P, Enjalbert A: D2 dopaminergic receptors: normal and abnormal transduction mechanisms. Horm Res 38: 78–83, 1992

    Google Scholar 

  79. Jaffe CA, Barkan AL: Acromegaly. Recognition and treatment. Drugs 47: 425–445, 1994

    Google Scholar 

  80. Greenman Y, Melmed S: Expression of three somatostatin receptor subtypes in pituitary adenomas: evidence for preferential SSTR5 expression in the mammosomatotroph lineage. J Clin Endocrinol Metab 79: 724–729, 1994

    Google Scholar 

  81. Miller GM, Alexander JM, Bikkal HA, Katznelson L, Zervas NT, Klibanski A: Somatostatin receptor subtype gene expression in pituitary adenomas. J Clin Endocrinol Metab 80: 1386–1392, 1995

    Google Scholar 

  82. Schaer JC, Waser B, Mengod G, Reubi JC: Somatostatin receptor subtypes sst1, sst2, sst3 and sst5 expression in human pituitary, gastroentero-pancreatic and mammary tumors: comparison of mRNA analysis with receptor autoradiography. Int J Cancer 70: 530–537, 1997

    Google Scholar 

  83. Pei L, Melmed S, Scheithauer B, Kovacs K, Prager D: H-ras mutations in human pituitary carcinoma metastases. J Clin Endocrinol Metab 78: 842–846, 1994

    Google Scholar 

  84. Todisco A, Seva C, Takeuchi Y, Dickinson CJ, Yamada T: Somatostatin inhibits AP-1 function via multiple protein phosphatases. Am J Physiol 269: G160–G166, 1995

    Google Scholar 

  85. Zhu J, Leon SP, Beggs AH, Busque L, Gilliland DG, Black PM: Human pituitary adenomas show no loss of heterozygosity at the retinoblastoma gene locus. J Clin Endocrinol Metab 78: 922–927, 1994

    Google Scholar 

  86. Lloyd RV, Jin L, Qian X, Kulig E: Aberrant p27Kip1 expression in endocrine and other tumors. Am J Pathol 150: 401–407, 1997

    Google Scholar 

  87. Scheithauer BW: Pathology of the pituitary and sellar region: exclusive of pituitary adenoma. Pathol Annu 1: 67–155, 1985

    Google Scholar 

  88. Capella C, Riva C, Leutner M, La Rosa S: Pituitary lesions in multiple endocrine neoplasia syndrome (MENS) type 1. Pathol Res Pract 191: 345–347, 1995

    Google Scholar 

  89. Chandrasekharappa SC, Guru SC, Manickam P, Olufemi SE, Collins FS, Emmertbuck MR, Debelenko LV, Zhuang ZP, Lubensky IA, Liotta LA, Crabtree JS, Wang YP, Roe BA, Weisemann J, Boguski MS, Agarwal SK, Kester MB, Kim YS, Heppner C, Dong QH, Spiegel AM, Burns AL, Marx SJ: Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 276: 404–407, 1997

    Google Scholar 

  90. Agarwal SK, Guru SC, Heppner C, Erdos MR, Collins RM, Park SY, Saggar S, Chandrasekharappa SC, Collins FS, Spiegel AM, Marx SJ, Burns AL: Menin interacts with the AP1 transcription factor JunD and represses JunDactivated transcription. Cell 96: 143–152, 1999

    Google Scholar 

  91. Heppner C, Kester MB, Agarwall SK, Debelenko LV, Emmert-Buck MR, Guru SC, Manickam P, Olufemi S-E, Skarulis MC, Doppman JL, Alexander RH, Kim YS, Sagger SK, Lubensky IA, Zhuang Z, Liotta LA, Chandrasekharappa SC, Collins FS, Spiegel AM, Burns AL, Marx SJ: Somatic mutation of the MEN1 gene in parathyroid tumours. Nat Genet 16: 375–378, 1997

    Google Scholar 

  92. Boggild MD, Jenkinson S, Pistorello M, Boscaro M, Scanarini M, McTernan P, Perrett CW, Thakker RV, Clayton RN: Molecular Genetic studies of sporadic pituitary tumors. J Clin Endocrinol Metab 78: 387–392, 1994

    Google Scholar 

  93. Eubanks PJ, Sawicki MP, Samara GJ, Gatti R, Nakamura Y, Tsao D, Johnson C, Hurwitz M, Wan YJ, Passaro EJ: Putative tumor-suppressor gene on chromosome 11 is important in sporadic endocrine tumor formation. Am J Surg 167: 180–185, 1994

    Google Scholar 

  94. Farrell WE, Simpson DJ, Bicknell J, Magnay JL, Kyrodimou E, Thakker RV, Clayton RN: Sequence analysis and transcript expression of the MEN1 gene in sporadic pituitary tumours. Br J Cancer 80: 44–50, 1999

    Google Scholar 

  95. Bates AS, Farrell WE, Bicknell EJ, McNicol AM, Talbot AJ, Broome JC, Perrett CW, Thakker RV, Clayton RN: Allelic deletion in pituitary adenomas reflects aggressive biological activity and has potential value as a prognostic marker. J Clin Endocrinol Metab 82: 818–824, 1997

    Google Scholar 

  96. Thakker RV, Pook MA, Wooding C, Boscaro M, Scanarini M, Clayton RN: Association of somatotrophinomas with loss of alleles on chromosome 11 and with gsp mutations. J Clin Invest 91: 2815–2821, 1993

    Google Scholar 

  97. Yoshimoto K, Iwahana H, Fukuda A, Sano T, Itakura M: Rare mutations of the Gs alpha subunit gene in human endocrine tumors. Mutation detection by polymerase chain reaction-primer-introduced restriction analysis. Cancer 72: 1386–1393, 1993

    Google Scholar 

  98. Williamson EA, Johnson SJ, Foster S, Kendall Taylor P, Harris PE: G protein gene mutations in patients with multiple endocrinopathies. J Clin Endocrinol Metab 80: 1702–1705, 1995

    Google Scholar 

  99. Kroemer G: The proto-oncogene Bcl-2 and its role in regulating apoptosis. Nat Med 3: 614–620, 1997

    Google Scholar 

  100. Reed JC: Double identity for proteins of the Bcl-2 family. Nature 387: 773–776, 1997

    Google Scholar 

  101. Zornig M, Evan GI: Cell cycle: on target with Myc. Curr Biol 6: 1553–1556, 1996

    Google Scholar 

  102. Wang DG, Johnston CF, Atkinson AB, Heaney AP, Mirakhur M, Buchanan KD: Expression of bcl-2 oncoprotein in pituitary tumours: comparison with c-myc. J Clin Pathol 49: 795–797, 1996

    Google Scholar 

  103. Ikeda H, Yoshimoto T: The relationship between c-myc protein expression, the bromodeoxyuridine labeling index and the biological behavior of pituitary adenomas. Acta Neuropathol (Berl) 83: 361–364, 1992

    Google Scholar 

  104. Herman V, Drazin NZ, Gonsky R, Melmed S: Molecular screening of pituitary adenomas for gene mutations and rearrangements. J Clin Endocrinol Metab 77: 50–55, 1993

    Google Scholar 

  105. Levy A, Hall L, Yeudall WA, Lightman SL: p53 gene mutations in pituitary adenomas: rare events. Clin Endocrinol (Oxf) 41: 809–814, 1994

    Google Scholar 

  106. Buckley N, Bates AS, Broome JC, Strange RC, Perrett CW, Burke CW, Clayton RN: p53 protein accumulates in Cushings adenomas and invasive non-functional adenomas. J Clin Endocrinol Metab 80: 692–696, 1995

    Google Scholar 

  107. Pernicone PJ, Scheithauer BW, Sebo TJ, Kovacs KT, Horvath E, Young WFJ, Lloyd RV, Davis DH, Guthrie BL, Schoene WC: Pituitary carcinoma: a clinicopathologic study of 15 cases. Cancer 79: 804–812, 1996

    Google Scholar 

  108. Egan SE, Weinberg RA: The pathway to signal achievement. Nature 365: 781–783, 1993

    Google Scholar 

  109. Campbell SL, Khosravi-Far R, Rossman KL, Clark GJ, Der CJ: Increasing complexity of Ras signaling. Oncogene 17: 1395–1413, 1998

    Google Scholar 

  110. Cai WY, Alexander JM, Hedley Whyte ET, Scheithauer BW, Jameson JL, Zervas NT, Klibanski A: ras mutations in human prolactinomas and pituitary carcinomas. J Clin Endocrinol Metab 78: 89–93, 1994

    Google Scholar 

  111. Amano O, Yoshitake Y, Nishikawa K, Iseki S: Immunocytochemical localization of basic fibroblast growth factor in the rat pituitary gland. Arch Histol Cytol 56: 269–276, 1993

    Google Scholar 

  112. Ezzat S, Smyth HS, Ramyar L, Asa SL: Heterogenous in vivo and in vitro expression of basic fibroblast growth factor by human pituitary adenomas. J Clin Endocrinol Metab 80: 878–884, 1995

    Google Scholar 

  113. Suzui H, Takahashi JA, Fukumoto M, Hashimoto N, Itoh N, Hatanaka M, Kikuchi H: Immunohistochemical study for basic fibroblast growth factor and fibroblast growth factor receptor I in pituitary adenomas. Neurosci Lett 171: 192–196, 1994

    Google Scholar 

  114. Inoue K, Sakai T, Hattori M: The cell-adhesive effect of basic fibroblast growth factor on pituitary cells in vitro. J Endocrinol 130: 381–386, 1991

    Google Scholar 

  115. Prysor Jones RA, Silverlight JJ, Jenkins JS: Oestradiol, vasoactive intestinal peptide and fibroblast growth factor in the growth of human pituitary tumour cells in vitro. J Endocrinol 120: 171–177, 1989

    Google Scholar 

  116. Gonsky R, Herman V, Melmed S, Fagin J: Transforming DNA sequences present in human prolactin-secreting pituitary tumors. Mol Endocrinol 5: 1687–1695, 1991

    Google Scholar 

  117. Shimon I, Huttner A, Said J, Spirina OM, Melmed S: Heparin-binding secretory transforming gene (hst) facilitates rat lactotrope cell tumorigenesis and induces prolactin gene transcription. J Clin Invest 97: 187–195, 1996

    Google Scholar 

  118. Abbass SA, Asa SL, Ezzat S: Altered expression of fibroblast growth factor receptors in human pituitary adenomas. J Clin Endocrinol Metab 82: 1160–1166, 1997

    Google Scholar 

  119. Chaidarun SS, Eggo MC, Sheppard MC, Stewart PM: Expression of epidermal growth factor (EGF), its receptor, and related oncoprotein (erbB-2) in human pituitary tumors and response to EGF in vitro. Endocrinology 135: 2012–2021, 1994

    Google Scholar 

  120. LeRiche VK, Asa SL, Ezzat S: Epidermal growth factor and its receptor (EGF-R) in human pituitary adenomas: EGF-R correlates with tumor aggressiveness. J Clin Endocrinol Metab 81: 656–662, 1996

    Google Scholar 

  121. Ezzat S, Walpola IA, Ramyar L, Smyth HS, Asa SL: Membrane-anchored expression of transforming growth factor-alpha in human pituitary adenoma cells. J Clin Endocrinol Metab 80: 534–539, 1995

    Google Scholar 

  122. McAndrew J, Paterson AJ, Asa SL, McCarthy KJ, Kudlow JE: Targeting of transforming growth factor-alpha expression to pituitary lactotrophs in transgenic mice results in selective lactotroph proliferation and adenomas. Endocrinology 136: 4479–4488, 1995

    Google Scholar 

  123. Park K, Kim SJ, Bang YJ, Park JG, Kim NK, Roberts AB, Sporn MB: Genetic changes in the transforming growth factor beta (TGF-beta) type II receptor gene in human gastric cancer cells: correlation with sensitivity to growth inhibition by TGF-beta. Proc Natl Acad Sci USA 91: 8772–8776, 1994

    Google Scholar 

  124. Ji H, Stout LE, Zhang Q, Zhang R, Leung HT, Leung BS: Absence of transforming growth factor-beta responsiveness in the tamoxifen growth-inhibited human breast cancer cell line CAMA-1. J Cell Biochem 54: 332–342, 1994

    Google Scholar 

  125. Hannon GJ, Beach D: p15INK4B is a potential effector of TGF-?-induced cell cycle arrest. Nature 371: 257–261, 1994

    Google Scholar 

  126. Green VL, Atkin SL, Speirs V, Jeffreys RV, Landolt AM, Mathew B, Hipkin L, White MC: Cytokine expression in human anterior pituitary adenomas. Clin Endocrinol (Oxf) 45: 179–185, 1996

    Google Scholar 

  127. Fujiwara K, Ikeda H, Yoshimoto T: Immunohistochemical demonstration of TGF-beta-receptor type II in human pituitary adenomas. Acta Histochem 97: 445–454, 1995

    Google Scholar 

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Authors and Affiliations

  1. Division of Cell Biology, Cancer Institute, Hokkaido University School of Medicine, Sapporo, Japan

    Mitsuhiro Tada & Tetsuya Moriuchi

  2. Department of Neurosurgery, Hokkaido University School of Medicine, Sapporo, Japan

    Hiroyuki Kobayashi

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  1. Mitsuhiro Tada
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  2. Hiroyuki Kobayashi
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  3. Tetsuya Moriuchi
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Tada, M., Kobayashi, H. & Moriuchi, T. Molecular Basis of Pituitary Oncogenesis. J Neurooncol 45, 83–96 (1999). https://doi.org/10.1023/A:1006390306336

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