Signaling Pathways Regulating Pituitary Lactotrope Homeostasis and Tumorigenesis

  • Allyson K. Booth
  • Arthur Gutierrez-HartmannEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 846)


Dysregulation of the signaling pathways that govern lactotrope biology contributes to tumorigenesis of prolactin (PRL)-secreting adenomas, or prolactinomas, leading to a state of pathological hyperprolactinemia. Prolactinomas cause hypogonadism, infertility, osteoporosis, and tumor mass effects, and are the most common type of neuroendocrine tumor. In this review, we highlight signaling pathways involved in lactotrope development, homeostasis, and physiology of pregnancy, as well as implications for signaling pathways in pathophysiology of prolactinoma. We also review mutations found in human prolactinoma and briefly discuss animal models that are useful in studying pituitary adenoma, many of which emphasize the fact that alterations in signaling pathways are common in prolactinomas. Although individual mutations have been proposed as possible driving forces for prolactinoma tumorigenesis in humans, no single mutation has been clinically identified as a causative factor for the majority of prolactinomas. A better understanding of lactotrope-specific responses to intracellular signaling pathways is needed to explain the mechanism of tumorigenesis in prolactinoma.


Prolactin Lactotrope Prolactinoma Tumorigenesis MAPK PI3K Signaling Pituitary 


  1. 1.
    Freeman ME, Kanyicska B, Lerant A, Nagy G (2000) Prolactin: structure, function, and regulation of secretion. Physiol Rev 80:1523–1631.PubMedGoogle Scholar
  2. 2.
    Horseman ND, Zhao W, Montecino-Rodriguez E, Tanaka M, Nakashima K, Engle SJ, Smith F, Markoff E, Dorshkind K (1997) Defective mammopoiesis, but normal hematopoiesis, in mice with a targeted disruption of the prolactin gene. EMBO J 16:6926–6935. doi:10.1093/emboj/16.23.6926PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Ormandy CJ, Camus A, Barra J, Damotte D, Lucas B, Buteau H, Edery M, Brousse N, Babinet C, Binart N, Kelly PA (1997) Null mutation of the prolactin receptor gene produces multiple reproductive defects in the mouse. Genes Dev 11:167–178PubMedCrossRefGoogle Scholar
  4. 4.
    Grosvenor CE, Whitworth N (1974) Evidence for a steady rate of secretion of prolactin following suckling in the rat. J Dairy Sci 57:900–904. doi:10.3168/jds.S0022-0302(74)84985-4PubMedCrossRefGoogle Scholar
  5. 5.
    Mena F, Grosvenor CE (1968) Effect of number of pups upon suckling-induced fall in pituitary prolactin concentration and milk ejection in the rat. Endocrinology 82:623–626. doi:10.1210/endo-82-3-623PubMedCrossRefGoogle Scholar
  6. 6.
    Ignacak A, Kasztelnik M, Sliwa T, Korbut RA, Rajda K, Guzik TJ (2012) Prolactin–not only lactotrophin. A “new” view of the “old” hormone. J Physiol Pharmacol 63:435–443PubMedGoogle Scholar
  7. 7.
    Ben-Jonathan N, Hnasko R (2001) Dopamine as a prolactin (PRL) inhibitor. Endocr Rev 22:724–763. doi:10.1210/er.22.6.724PubMedCrossRefGoogle Scholar
  8. 8.
    Albert PR, Neve KA, Bunzow JR, Civelli O (1990) Coupling of a cloned rat dopamine-D2 receptor to inhibition of adenylyl cyclase and prolactin secretion. J Biol Chem 265:2098–2104PubMedGoogle Scholar
  9. 9.
    Lew AM, Yao H, Elsholtz HP (1994) 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 269:12007–12013PubMedGoogle Scholar
  10. 10.
    Liu JC, Baker RE, Sun C, Sundmark VC, Elsholtz HP (2002) Activation of Go-coupled dopamine D2 receptors inhibits ERK1/ERK2 in pituitary cells. A key step in the transcriptional suppression of the prolactin gene. J Biol Chem 277:35819–35825. doi:10.1074/jbc.M202920200PubMedCrossRefGoogle Scholar
  11. 11.
    Banihashemi B, Albert PR (2002) Dopamine-D2S receptor inhibition of calcium influx, adenylyl cyclase, and mitogen-activated protein kinase in pituitary cells: distinct Galpha and Gbetagamma requirements. Mol Endocrinol 16:2393–2404. doi:10.1210/me.2001-0220PubMedCrossRefGoogle Scholar
  12. 12.
    Minami S, Sarkar DK (1997) Transforming growth factor-beta 1 inhibits prolactin secretion and lactotropic cell proliferation in the pituitary of oestrogen-treated Fischer 344 rats. Neurochem Int 30:499–506PubMedCrossRefGoogle Scholar
  13. 13.
    Sarkar DK, Chaturvedi K, Oomizu S, Boyadjieva NI, Chen CP (2005) Dopamine, dopamine D2 receptor short isoform, transforming growth factor (TGF)-beta1, and TGF-beta type II receptor interact to inhibit the growth of pituitary lactotropes. Endocrinology 146:4179–4188. doi:10.1210/en.2005-0430PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Chaturvedi K, Sarkar DK (2005) Mediation of basic fibroblast growth factor-induced lactotropic cell proliferation by Src-Ras-mitogen-activated protein kinase p44/42 signaling. Endocrinology 146:1948–1955. doi:10.1210/en.2004-1448PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Hentges S, Boyadjieva N, Sarkar DK (2000) Transforming growth factor-beta3 stimulates lactotrope cell growth by increasing basic fibroblast growth factor from folliculo-stellate cells. Endocrinology 141:859–867. doi:10.1210/endo.141.3.7382PubMedGoogle Scholar
  16. 16.
    Hentges S, Sarkar DK (2001) Transforming growth factor-beta regulation of estradiol-induced prolactinomas. Front Neuroendocrinol 22:340–363. doi:10.1006/frne.2001.0220PubMedCrossRefGoogle Scholar
  17. 17.
    Sarkar DK (2006) Genesis of prolactinomas: studies using estrogen-treated animals. Front Horm Res 35:32–49. doi:10.1159/000094307PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Spada A, Mantovani G, Lania A (2005) Pathogenesis of prolactinomas. Pituitary 8:7–15. doi:10.1007/s11102-005-5080-7PubMedCrossRefGoogle Scholar
  19. 19.
    Beshay VE, Beshay JE, Halvorson LM (2007) Pituitary tumors: diagnosis, management, and implications for reproduction. Semin Reprod Med 25:388–401. doi:10.1055/s-2007-984745PubMedCrossRefGoogle Scholar
  20. 20.
    Ezzat S, Asa SL, Couldwell WT, Barr CE, Dodge WE, Vance ML, McCutcheon IE (2004) The prevalence of pituitary adenomas: a systematic review. Cancer 101:613–619. doi:10.1002/cncr.20412PubMedCrossRefGoogle Scholar
  21. 21.
    Scully KM, Rosenfeld MG (2002) Pituitary development: regulatory codes in mammalian organogenesis. Science 295:2231–2235. doi:10.1126/science.1062736PubMedCrossRefGoogle Scholar
  22. 22.
    Takuma N, Sheng HZ, Furuta Y, Ward JM, Sharma K, Hogan BL, Pfaff SL, Westphal H, Kimura S, Mahon KA (1998) Formation of Rathke’s Rathke’s pouch requires dual induction from the diencephalon. Development 125:4835–4840PubMedGoogle Scholar
  23. 23.
    Watkins-Chow DE, Camper SA (1998) How many homeobox genes does it take to make a pituitary gland? Trends Genet 14:284–290PubMedCrossRefGoogle Scholar
  24. 24.
    Bradford AP, Conrad KE, Wasylyk C, Wasylyk B, Gutierrez-Hartmann A (1995) Functional interaction of c-Ets-1 and GHF-1/Pit-1 mediates Ras activation of pituitary-specific gene expression: mapping of the essential c-Ets-1 domain. Mol Cell Biol 15:2849–2857PubMedCentralPubMedGoogle Scholar
  25. 25.
    Bradford AP, Wasylyk C, Wasylyk B, Gutierrez-Hartmann A (1997) Interaction of Ets-1 and the POU-homeodomain protein GHF-1/Pit-1 reconstitutes pituitary-specific gene expression. Mol Cell Biol 17:1065–1074PubMedCentralPubMedGoogle Scholar
  26. 26.
    Bradford AP, Brodsky KS, Diamond SE, Kuhn LC, Liu Y, Gutierrez-Hartmann A (2000) The Pit-1 homeodomain and beta-domain interact with Ets-1 and modulate synergistic activation of the rat prolactin promoter. J Biol Chem 275:3100–3106. doi:10.1074/jbc.275.5.3100PubMedCrossRefGoogle Scholar
  27. 27.
    Vankelecom H (2010) Pituitary stem/progenitor cells: embryonic players in the adult gland? Eur J Neurosci 32:2063–2081. doi:10.1111/j.1460-9568.2010.07523.xPubMedCrossRefGoogle Scholar
  28. 28.
    Fauquier T, Rizzoti K, Dattani M, Lovell-Badge R, Robinson ICAF (2008) SOX2-expressing progenitor cells generate all of the major cell types in the adult mouse pituitary gland. Proc Natl Acad Sci U S A 105:2907–2912. doi:10.1073/pnas.0707886105PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Gleiberman AS, Michurina T, Encinas JM, Roig JL, Krasnov P, Balordi F, Fishell G, Rosenfeld MG, Enikolopov G (2008) Genetic approaches identify adult pituitary stem cells. Proc Natl Acad Sci U S A 105:6332–6337. doi:10.1073/pnas.0801644105PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Garcia-Lavandeira M, Quereda V, Flores I, Saez C, Diaz-Rodriguez E, Japon MA, Ryan AK, Blasco MA, Dieguez C, Malumbres M, Alvarez CV (2009) A GRFa2/Prop1/stem (GPS) cell niche in the pituitary. PLoS ONE 4:e4815. doi:10.1371/journal.pone.0004815PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Chen J, Hersmus N, Van Duppen V, Caesens P, Denef C, Vankelecom H (2005) The adult pituitary contains a cell population displaying stem/progenitor cell and early embryonic characteristics. Endocrinology 146:3985–3998. doi:10.1210/en.2005-0185PubMedCrossRefGoogle Scholar
  32. 32.
    Vankelecom H, Chen J (2014) Pituitary stem cells: where do we stand? Mol Cell Endocrinol 385:2–17. doi:10.1016/j.mce.2013.08.018PubMedCrossRefGoogle Scholar
  33. 33.
    Frawley LS, Boockfor FR (1991) Mammosomatotropes: presence and functions in normal and neoplastic pituitary tissue. Endocr Rev 12:337–355. doi:10.1210/edrv-12-4-337PubMedCrossRefGoogle Scholar
  34. 34.
    Cuny T, Gerard C, Saveanu A, Barlier A, Enjalbert A (2011) Physiopathology of somatolactotroph cells: from transduction mechanisms to cotargeting therapy. Ann N Y Acad Sci 1220:60–70. doi:10.1111/j.1749-6632.2010.05924.xPubMedCrossRefGoogle Scholar
  35. 35.
    Kineman RD, Faught WJ, Frawley LS (1992) The ontogenic and functional relationships between growth hormone- and prolactin-releasing cells during the development of the bovine pituitary. J Endocrinol 134:91–96PubMedCrossRefGoogle Scholar
  36. 36.
    Kineman RD, Henricks DM, Faught WJ, Frawley LS (1991) Fluctuations in the proportions of growth hormone- and prolactin-secreting cells during the bovine estrous cycle. Endocrinology 129:1221–1225. doi:10.1210/endo-129-3-1221PubMedCrossRefGoogle Scholar
  37. 37.
    Conrad KE, Gutierrez-Hartmann A (1992) The ras and protein kinase A pathways are mutually antagonistic in regulating rat prolactin promoter activity. Oncogene 7:1279–1286PubMedGoogle Scholar
  38. 38.
    Keech CA, Jackson SM, Siddiqui SK, Ocran KW, Gutierrez-Hartmann A (1992) Cyclic adenosine 3′, 5′5′-monophosphate activation of the rat prolactin promoter is restricted to the pituitary-specific cell type. Mol Endocrinol 6:2059–2070. doi:10.1210/mend.6.12.1337142PubMedGoogle Scholar
  39. 39.
    Gutierrez-Hartmann A, Duval DL, Bradford AP (2007) ETS transcription factors in endocrine systems. Trends Endocrinol Metab 18:150–158. doi:10.1016/j.tem.2007.03.002PubMedCrossRefGoogle Scholar
  40. 40.
    Tuteja N (2009) Signaling through G protein coupled receptors. Plant Signal Behav 4:942–947PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Penela P, Nogués L, Mayor F (2014) Role of G protein-coupled receptor kinases in cell migration. Curr Opin Cell Biol 27:10–17. doi:10.1016/ Scholar
  42. 42.
    Lamberts SW, Macleod RM (1990) Regulation of prolactin secretion at the level of the lactotroph. Physiol Rev 70:279–318PubMedGoogle Scholar
  43. 43.
    Arbogast LA, Voogt JL (1991) Mechanisms of tyrosine hydroxylase regulation during pregnancy: evidence for protein dephosphorylation during the prolactin surges. Endocrinology 129:2575–2582. doi:10.1210/endo-129-5-2575PubMedCrossRefGoogle Scholar
  44. 44.
    Pasqualini C, Guibert B, Leviel V (1993) Short-term inhibitory effect of estradiol on tyrosine hydroxylase activity in tuberoinfundibular dopaminergic neurons in vitro. J Neurochem 60:1707–1713PubMedCrossRefGoogle Scholar
  45. 45.
    Nagy GM, DeMaria JE, Freeman ME (1998) Changes in the local metabolism of dopamine in the anterior and neural lobes but not in the intermediate lobe of the pituitary gland during nursing. Brain Res 790:315–317PubMedCrossRefGoogle Scholar
  46. 46.
    De Greef WJ, Plotsky PM, Neill JD (1981) Dopamine levels in hypophysial stalk plasma and prolactin levels in peripheral plasma of the lactating rat: effects of a simulated suckling stimulus. Neuroendocrinology 32:229–233PubMedCrossRefGoogle Scholar
  47. 47.
    Radl D, De Mei C, Chen E, Lee H, Borrelli E (2013) Each individual isoform of the dopamine D2 receptor protects from lactotroph hyperplasia. Mol Endocrinol 27:953–965. doi:10.1210/me.2013-1008PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Dhillon AS, Hagan S, Rath O, Kolch W (2007) MAP kinase signalling pathways in cancer. Oncogene 26:3279–3290. doi:10.1038/sj.onc.1210421PubMedCrossRefGoogle Scholar
  49. 49.
    Pertuit M, Romano D, Zeiller C, Barlier A, Enjalbert A, Gerard C (2011) The gsp oncogene disrupts Ras/ERK-dependent prolactin gene regulation in gsp inducible somatotroph cell line. Endocrinology 152:1234–1243. doi:10.1210/en.2010-1077PubMedCrossRefGoogle Scholar
  50. 50.
    Wang YH, Maurer RA (1999) A role for the mitogen-activated protein kinase in mediating the ability of thyrotropin-releasing hormone to stimulate the prolactin promoter. Mol Endocrinol 13:1094–1104. doi:10.1210/mend.13.7.0315PubMedCrossRefGoogle Scholar
  51. 51.
    Romano D, Magalon K, Ciampini A, Talet C, Enjalbert A, Gerard C (2003) Differential involvement of the Ras and Rap1 small GTPases in vasoactive intestinal and pituitary adenylyl cyclase activating polypeptides control of the prolactin gene. J Biol Chem 278:51386–51394. doi:10.1074/jbc.M308372200PubMedCrossRefGoogle Scholar
  52. 52.
    Murphy LO, Blenis J (2006) MAPK signal specificity: the right place at the right time. Trends Biochem Sci 31:268–275. doi:10.1016/j.tibs.2006.03.009PubMedCrossRefGoogle Scholar
  53. 53.
    Watters JJ, Chun TY, Kim YN, Bertics PJ, Gorski J (2000) Estrogen modulation of prolactin gene expression requires an intact mitogen-activated protein kinase signal transduction pathway in cultured rat pituitary cells. Mol Endocrinol 14:1872–1881. doi:10.1210/mend.14.11.0551PubMedCrossRefGoogle Scholar
  54. 54.
    Bradford AP, Conrad KE, Tran PH, Ostrowski MC, Gutierrez-Hartmann A (1996) GHF-1/Pit-1 functions as a cell-specific integrator of Ras signaling by targeting the Ras pathway to a composite Ets-1/GHF-1 response element. J Biol Chem 271:24639–24648. doi:10.1074/jbc.271.40.24639PubMedCrossRefGoogle Scholar
  55. 55.
    Schweppe RE, Gutierrez-Hartmann A (2001) Pituitary Ets-1 and GABP bind to the growth factor regulatory sites of the rat prolactin promoter. Nucleic Acids Res 29:1251–1260PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Schweppe RE, Melton AA, Brodsky KS, Aveline LD, Resing KA, Ahn NG, Gutierrez-Hartmann A (2003) Purification and mass spectrometric identification of GA-binding protein (GABP) as the functional pituitary Ets factor binding to the basal transcription element of the prolactin promoter. J Biol Chem 278:16863–16872. doi:10.1074/jbc.M213063200PubMedCrossRefGoogle Scholar
  57. 57.
    Oomizu S, Chaturvedi K, Sarkar DK (2004) Folliculostellate cells determine the susceptibility of lactotropes to estradiol’s mitogenic action. Endocrinology 145:1473–1480. doi:10.1210/en.2003-0965PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Hubina E, Nanzer AM, Hanson MR, Ciccarelli E, Losa M, Gaia D, Papotti M, Terreni MR, Khalaf S, Jordan S, Czirják S, Hanzély Z, Nagy GM, Góth MI, Grossman AB, Korbonits M (2006) Somatostatin analogues stimulate p27 expression and inhibit the MAP kinase pathway in pituitary tumours. Eur J Endocrinol 155:371–379. doi:10.1530/eje.1.02213PubMedCrossRefGoogle Scholar
  59. 59.
    Schonbrunn A, Krasnoff M, Westendorf JM, Tashjian AH (1980) Epidermal growth factor and thyrotropin-releasing hormone act similarly on a clonal pituitary cell strain. Modulation of hormone production and inhbition of cell proliferation. J Cell Biol 85:786–797PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Johnson LK, Baxter JD, Vlodavsky I, Gospodarowicz D (1980) Epidermal growth factor and expression of specific genes: effects on cultured rat pituitary cells are dissociable from the mitogenic response. Proc Natl Acad Sci U S A 77:394–398PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Ramsdell JS (1991) Transforming growth factor-alpha and -beta are potent and effective inhibitors of GH4 pituitary tumor cell proliferation. Endocrinology 128:1981–1990. doi:10.1210/endo-128-4-1981PubMedCrossRefGoogle Scholar
  62. 62.
    Ramsdell JS (1990) Thyrotropin-releasing hormone inhibits GH4 pituitary cell proliferation by blocking entry into S phase. Endocrinology 126:472–479. doi:10.1210/endo-126-1-472PubMedCrossRefGoogle Scholar
  63. 63.
    Felix R, Meza U, Cota G (1995) Induction of classical lactotropes by epidermal growth factor in rat pituitary cell cultures. Endocrinology 136:939–946. doi:10.1210/endo.136.3.7867603PubMedGoogle Scholar
  64. 64.
    Nakagawa T, Mabry M, de Bustros A, Ihle JN, Nelkin BD, Baylin SB (1987) Introduction of v-Ha-ras oncogene induces differentiation of cultured human medullary thyroid carcinoma cells. Proc Natl Acad Sci U S A 84:5923–5927PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Bar-Sagi D, Feramisco JR (1985) Microinjection of the ras oncogene protein into PC12 cells induces morphological differentiation. Cell 42:841–848PubMedCrossRefGoogle Scholar
  66. 66.
    McCubrey JA, Steelman LS, Abrams SL, Lee JT, Chang F, Bertrand FE, Navolanic PM, Terrian DM, Franklin RA, D’Assoro AB, Salisbury JL, Mazzarino MC, Stivala F, Libra M (2006) Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul 46:249–279. doi:10.1016/j.advenzreg.2006.01.004PubMedCrossRefGoogle Scholar
  67. 67.
    Yajima I, Kumasaka MY, Thang ND, Goto Y, Takeda K, Yamanoshita O, Iida M, Ohgami N, Tamura H, Kawamoto Y, Kato M (2012) RAS/RAF/MEK/ERK and PI3K/PTEN/AKT signaling in malignant melanoma progression and therapy. Dermatol Res Pract 2012:354191. doi:10.1155/2012/354191PubMedCentralPubMedGoogle Scholar
  68. 68.
    Dworakowska D, Wlodek E, Leontiou CA, Igreja S, Cakir M, Teng M, Prodromou N, Góth MI, Grozinsky-Glasberg S, Gueorguiev M, Kola B, Korbonits M, Grossman AB (2009) Activation of RAF/MEK/ERK and PI3K/AKT/mTOR pathways in pituitary adenomas and their effects on downstream effectors. Endocr Relat Cancer 16:1329–1338. doi:10.1677/ERC-09-0101PubMedCrossRefGoogle Scholar
  69. 69.
    Rubinfeld H, Shimon I (2012) PI3K/Akt/mTOR and Raf/MEK/ERK signaling pathways perturbations in non-functioning pituitary adenomas. Endocr 42:285–291. doi:10.1007/s12020-012-9682-3CrossRefGoogle Scholar
  70. 70.
    Karreth FA, Tuveson DA (2009) Modelling oncogenic Ras/Raf signalling in the mouse. Curr Opin Genet Dev 19:4–11. doi:10.1016/j.gde.2008.12.006PubMedCentralPubMedCrossRefGoogle Scholar
  71. 71.
    McAndrew J, Paterson AJ, Asa SL, McCarthy KJ, Kudlow JE (1995) Targeting of transforming growth factor-alpha expression to pituitary lactotrophs in transgenic mice results in selective lactotroph proliferation and adenomas. Endocrinology 136:4479–4488. doi:10.1210/endo.136.10.7664668PubMedGoogle Scholar
  72. 72.
    Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, González-Barón M (2004) PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 30:193–204. doi:10.1016/j.ctrv.2003.07.007PubMedCrossRefGoogle Scholar
  73. 73.
    Vender JR, Laird MD, Dhandapani KM (2008) Inhibition of NFkappaB reduces cellular viability in GH3 pituitary adenoma cells. Neurosurgery 62:1122–1127; discussion 1027–8. doi:10.1227/01.neu.0000325874.82999.75Google Scholar
  74. 74.
    Sukumari-Ramesh S, Singh N, Dhandapani KM, Vender JR (2011) mTOR inhibition reduces cellular proliferation and sensitizes pituitary adenoma cells to ionizing radiation. Surg Neurol Int 2:22. doi:10.4103/2152-7806.77029PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    Romano D, Pertuit M, Rasolonjanahary R, Barnier J-V, Magalon K, Enjalbert A, Gerard C (2006) Regulation of the RAP1/RAF-1/extracellularly regulated kinase-1/2 cascade and prolactin release by the phosphoinositide 3-kinase/AKT pathway in pituitary cells. Endocrinology 147:6036–6045. doi:10.1210/en.2006-0325PubMedCrossRefGoogle Scholar
  76. 76.
    Cakir M, Grossman AB (2009) Targeting MAPK (Ras/ERK) and PI3K/Akt pathways in pituitary tumorigenesis. Expert Opin Ther Targets 13:1121–1134. doi:10.1517/14728220903170675PubMedCrossRefGoogle Scholar
  77. 77.
    Borrelli E, Sawchenko PE, Evans RM (1992) Pituitary hyperplasia induced by ectopic expression of nerve growth factor. Proc Natl Acad Sci U S A 89:2764–2768PubMedCentralPubMedCrossRefGoogle Scholar
  78. 78.
    Roh M, Paterson AJ, Asa SL, Chin E, Kudlow JE (2001) Stage-sensitive blockade of pituitary somatomammotrope development by targeted expression of a dominant negative epidermal growth factor receptor in transgenic mice. Mol Endocrinol 15:600–613. doi:10.1210/mend.15.4.0625PubMedCrossRefGoogle Scholar
  79. 79.
    Ezzat S, Zheng L, Zhu X, Wu GE, Asa SL (2002) Targeted expression of a human pituitary tumor- derived isoform of FGF receptor-4 recapitulates pituitary tumorigenesis. 109:15–16. doi:10.1172/JCI200214036.IntroductionGoogle Scholar
  80. 80.
    Sarkisian CJ, Keister BA, Stairs DB, Boxer RB, Moody SE, Chodosh LA (2007) Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis. Nat Cell Biol 9:493–505. doi:10.1038/ncb1567PubMedCrossRefGoogle Scholar
  81. 81.
    Daikoku T, Hirota Y, Tranguch S, Joshi AR, DeMayo FJ, Lydon JP, Ellenson LH, Dey SK (2008) Conditional loss of uterine Pten unfailingly and rapidly induces endometrial cancer in mice. Cancer Res 68:5619–5627. doi:10.1158/0008-5472.CAN-08-1274PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    Iwanaga K, Yang Y, Raso MG, Ma L, Hanna AE, Thilaganathan N, Moghaddam S, Evans CM, Li H, Cai W-W, Sato M, Minna JD, Wu H, Creighton CJ, Demayo FJ, Wistuba II, Kurie JM (2008) Pten inactivation accelerates oncogenic K-ras-initiated tumorigenesis in a mouse model of lung cancer. Cancer Res 68:1119–1127. doi:10.1158/0008-5472.CAN-07-3117PubMedCentralPubMedCrossRefGoogle Scholar
  83. 83.
    Gire V, Marshall CJ, Wynford-Thomas D (1999) Activation of mitogen-activated protein kinase is necessary but not sufficient for proliferation of human thyroid epithelial cells induced by mutant Ras. Oncogene 18:4819–4832. doi:10.1038/sj.onc.1202857PubMedCrossRefGoogle Scholar
  84. 84.
    Gire V, Marshall C, Wynford-Thomas D (2000) PI-3-kinase is an essential anti-apoptotic effector in the proliferative response of primary human epithelial cells to mutant RAS. Oncogene 19:2269–2276. doi:10.1038/sj.onc.1203544PubMedCrossRefGoogle Scholar
  85. 85.
    Fan H-Y, Liu Z, Paquet M, Wang J, Lydon JP, DeMayo FJ, Richards JS (2009) Cell type-specific targeted mutations of Kras and Pten document proliferation arrest in granulosa cells versus oncogenic insult to ovarian surface epithelial cells. Cancer Res 69:6463–6472. doi:10.1158/0008-5472.CAN-08-3363PubMedCentralPubMedCrossRefGoogle Scholar
  86. 86.
    Fan H-Y, Richards JS (2010) Minireview: physiological and pathological actions of RAS in the ovary. Mol Endocrinol 24:286–298. doi:10.1210/me.2009-0251PubMedCentralPubMedCrossRefGoogle Scholar
  87. 87.
    Shi Y, Massagué J (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113:685–700PubMedCrossRefGoogle Scholar
  88. 88.
    Hentges S, Pastorcic M, De A, Boyadjieva N, Sarkar DK (2000) Opposing actions of two transforming growth factor-beta isoforms on pituitary lactotropic cell proliferation. Endocrinology 141:1528–1535. doi:10.1210/endo.141.4.7419PubMedGoogle Scholar
  89. 89.
    Farrow KN, Gutierrez-Hartmann A (1999) Transforming growth factor-beta1 inhibits rat prolactin promoter activity in GH4 neuroendocrine cells. DNA Cell Biol 18:863–873. doi:10.1089/104454999314863PubMedCrossRefGoogle Scholar
  90. 90.
    Lacerte A, Lee E-H, Reynaud R, Canaff L, De Guise C, Devost D, Ali S, Hendy GN, Lebrun J-J (2004) Activin inhibits pituitary prolactin expression and cell growth through Smads, Pit-1 and menin. Mol Endocrinol 18:1558–1569. doi:10.1210/me.2003-0470PubMedCrossRefGoogle Scholar
  91. 91.
    Harvey KF, Zhang X, Thomas DM (2013) The Hippo pathway and human cancer. Nat Rev Cancer 13:246–257. doi:10.1038/nrc3458PubMedCrossRefGoogle Scholar
  92. 92.
    Camargo FD, Gokhale S, Johnnidis JB, Fu D, Bell GW, Jaenisch R, Brummelkamp TR (2007) YAP1 increases organ size and expands undifferentiated progenitor cells. Curr Biol 17:2054–2060. doi:10.1016/j.cub.2007.10.039PubMedCrossRefGoogle Scholar
  93. 93.
    Chen Q, Zhang N, Gray RS, Li H, Ewald AJ, Zahnow CA, Pan D (2014) A temporal requirement for Hippo signaling in mammary gland differentiation, growth, and tumorigenesis. Genes Dev 28:432–437. doi:10.1101/gad.233676.113PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    St John MA, Tao W, Fei X, Fukumoto R, Carcangiu ML, Brownstein DG, Parlow AF, McGrath J, Xu T (1999) Mice deficient of Lats1 develop soft-tissue sarcomas, ovarian tumours and pituitary dysfunction. Nat Genet 21:182–186. doi:10.1038/5965Google Scholar
  95. 95.
    Battistutta R, Lolli G (2011) Structural and functional determinants of protein kinase CK2α: facts and open questions. Mol Cell Biochem 356:67–73. doi:10.1007/s11010-011-0939-6PubMedCrossRefGoogle Scholar
  96. 96.
    Karga HJ, Alexander JM, Hedley-Whyte ET, Klibanski A, Jameson JL (1992) Ras mutations in human pituitary tumors. J Clin Endocrinol Metab 74:914–919. doi:10.1210/jcem.74.4.1312542PubMedCrossRefGoogle Scholar
  97. 97.
    Herman V, Drazin NZ, Gonsky R, Melmed S (1993) Molecular screening of pituitary adenomas for gene mutations and rearrangements. J Clin Endocrinol Metab 77:50–55. doi:10.1210/jcem.77.1.8100831PubMedGoogle Scholar
  98. 98.
    Cai WY, Alexander JM, Hedley-Whyte ET, Scheithauer BW, Jameson JL, Zervas NT, Klibanski A (1994) ras mutations in human prolactinomas and pituitary carcinomas. J Clin Endocrinol Metab 78:89–93. doi:10.1210/jcem.78.1.8288721PubMedGoogle Scholar
  99. 99.
    Gürlek A, Karavitaki N, Ansorge O, Wass JA (2007) What are the markers of aggressiveness in prolactinomas? Changes in cell biology, extracellular matrix components, angiogenesis and genetics. Eur J Endocrinol 156:143–153. doi:10.1530/eje.1.02339PubMedCrossRefGoogle Scholar
  100. 100.
    Ewing I, Pedder-Smith S, Franchi G, Ruscica M, Emery M, Vax V, Garcia E, Czirják S, Hanzély Z, Kola B, Korbonits M, Grossman AB (2007) A mutation and expression analysis of the oncogene BRAF in pituitary adenomas. Clin Endocrinol (Oxf) 66:348–352. doi:10.1111/j.1365-2265.2006.02735.xCrossRefGoogle Scholar
  101. 101.
    Balasubramanian D, Scacheri PC (2009) Functional studies of menin through genetic manipulation of the Men1 homolog in mice. Adv Exp Med Biol 668:105–115PubMedCrossRefGoogle Scholar
  102. 102.
    Hughes E, Huang C (2011) Participation of Akt, menin, and p21 in pregnancy-induced beta-cell proliferation. Endocrinology 152:847–855. doi:10.1210/en.2010-1250PubMedCrossRefGoogle Scholar
  103. 103.
    Biondi CA, Gartside MG, Waring P, Loffler KA, Stark MS, Magnuson MA, Kay GF, Hayward NK (2004) Conditional inactivation of the MEN1 gene leads to pancreatic and pituitary tumorigenesis but does not affect normal development of these tissues. Mol Cell Biol 24:3125–3131PubMedCentralPubMedCrossRefGoogle Scholar
  104. 104.
    Crabtree JS, Scacheri PC, Ward JM, Garrett-Beal L, Emmert-Buck MR, Edgemon KA, Lorang D, Libutti SK, Chandrasekharappa SC, Marx SJ, Spiegel AM, Collins FS (2001) A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors. Proc Natl Acad Sci U S A 98:1118–1123. doi:10.1073/pnas.98.3.1118PubMedCentralPubMedCrossRefGoogle Scholar
  105. 105.
    Marini F, Falchetti A, Del Monte F, Carbonell Sala S, Gozzini A, Luzi E, Brandi ML (2006) Multiple endocrine neoplasia type 1. Orphanet J Rare Dis 1:38. doi:10.1186/1750-1172-1-38PubMedCentralPubMedCrossRefGoogle Scholar
  106. 106.
    Poncin J, Stevenaert A, Beckers A (1999) Somatic MEN1 gene mutation does not contribute significantly to sporadic pituitary tumorigenesis. Eur J Endocrinol 140:573–576PubMedCrossRefGoogle Scholar
  107. 107.
    Sakamoto H, Mori M, Taira M, Yoshida T, Matsukawa S, Shimizu K, Sekiguchi M, Terada M, Sugimura T (1986) Transforming gene from human stomach cancers and a noncancerous portion of stomach mucosa. Proc Natl Acad Sci U S A 83:3997–4001PubMedCentralPubMedCrossRefGoogle Scholar
  108. 108.
    Gonsky R, Herman V, Melmed S, Fagin J (1991) Transforming DNA sequences present in human prolactin-secreting pituitary tumors. Mol Endocrinol 5:1687–1695. doi:10.1210/mend-5-11-1687PubMedCrossRefGoogle Scholar
  109. 109.
    Shimon I, Hinton DR, Weiss MH, Melmed S (1998) Prolactinomas express human heparin-binding secretory transforming gene (hst) protein product: marker of tumour invasiveness. Clin Endocrinol (Oxf) 48:23–29CrossRefGoogle Scholar
  110. 110.
    Zhang X, Horwitz GA, Heaney AP, Nakashima M, Prezant TR, Bronstein MD, Melmed S (1999) Pituitary tumor transforming gene (PTTG) expression in pituitary adenomas. J Clin Endocrinol Metab 84:761–767PubMedCrossRefGoogle Scholar
  111. 111.
    Karhu A, Aaltonen LA (2007) Susceptibility to pituitary neoplasia related to MEN-1, CDKN1B and AIP mutations: an update. Hum Mol Genet 16 Spec No:R73–9. doi:10.1093/hmg/ddm036Google Scholar
  112. 112.
    Boikos SA, Stratakis CA (2007) Molecular genetics of the cAMP-dependent protein kinase pathway and of sporadic pituitary tumorigenesis. Hum Mol Genet 16 Spec No:R80–7. doi:10.1093/hmg/ddm019Google Scholar
  113. 113.
    Davis SW, Ellsworth BS, Peréz Millan MI, Gergics P, Schade V, Foyouzi N, Brinkmeier ML, Mortensen AH, Camper SA (2013) Pituitary gland development and disease: from stem cell to hormone production. Curr Top Dev Biol 106:1–47. doi:10.1016/B978-0-12-416021-7.00001-8PubMedCentralPubMedCrossRefGoogle Scholar
  114. 114.
    Akintoye SO, Chebli C, Booher S, Feuillan P, Kushner H, Leroith D, Cherman N, Bianco P, Wientroub S, Robey PG, Collins MT (2002) Characterization of gsp-mediated growth hormone excess in the context of McCune-Albright syndrome. J Clin Endocrinol Metab 87:5104–5112PubMedCrossRefGoogle Scholar
  115. 115.
    Lania AG, Ferrero S, Pivonello R, Mantovani G, Peverelli E, Di Sarno A, Beck-Peccoz P, Spada A, Colao A (2010) Evolution of an aggressive prolactinoma into a growth hormone secreting pituitary tumor coincident with GNAS gene mutation. J Clin Endocrinol Metab 95:13–17. doi:10.1210/jc.2009-1360PubMedCrossRefGoogle Scholar
  116. 116.
    Evans C-O, Moreno CS, Zhan X, McCabe MT, Vertino PM, Desiderio DM, Oyesiku NM (2008) Molecular pathogenesis of human prolactinomas identified by gene expression profiling, RT-qPCR, and proteomic analyses. Pituitary 11:231–245. doi:10.1007/s11102-007-0082-2PubMedCrossRefGoogle Scholar
  117. 117.
    Levy A (2008) Molecular and trophic mechanisms of tumorigenesis. Endocrinol Metab Clin North Am 37:23–50, vii. doi:10.1016/j.ecl.2007.10.009Google Scholar
  118. 118.
    Cristina C, García-Tornadú I, Díaz-Torga G, Rubinstein M, Low MJ, Becú-Villalobos D (2006) Dopaminergic D2 receptor knockout mouse: an animal model of prolactinoma. Front Horm Res 35:50–63. doi:10.1159/000094308PubMedCrossRefGoogle Scholar
  119. 119.
    Nakayama K, Ishida N, Shirane M, Inomata A, Inoue T, Shishido N, Horii I, Loh DY (1996) Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell 85:707–720PubMedCrossRefGoogle Scholar
  120. 120.
    Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA, Weinberg RA (1992) Effects of an Rb mutation in the mouse. Nature 359:295–300. doi:10.1038/359295a0PubMedCrossRefGoogle Scholar
  121. 121.
    Tsai KY, MacPherson D, Rubinson DA, Nikitin AY, Bronson R, Mercer KL, Crowley D, Jacks T (2002) ARF mutation accelerates pituitary tumor development in Rb+/− mice. Proc Natl Acad Sci U S A 99:16865–16870. doi:10.1073/pnas.262499599PubMedCentralPubMedCrossRefGoogle Scholar
  122. 122.
    Balasubramanian D, Scacheri PC (2009) Functional studies of menin through genetic manipulation of the Men1 homolog in mice. Adv Exp Med Biol 668:105–115PubMedCrossRefGoogle Scholar
  123. 123.
    Moons DS, Jirawatnotai S, Parlow AF, Gibori G, Kineman RD, Kiyokawa H (2002) Pituitary hypoplasia and lactotroph dysfunction in mice deficient for cyclin-dependent kinase-4. Endocrinology 143:3001–3008. doi:10.1210/endo.143.8.8956PubMedCrossRefGoogle Scholar

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© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Program in Reproductive Sciences and Integrated PhysiologyUniversity of Colorado Denver Anschutz Medical CampusAuroraUSA
  2. 2.Departments of Medicine and of Biochemistry and Molecular GeneticsUniversity of Colorado Denver Anschutz Medical CampusAuroraUSA

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