Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Pathogenesis of pituitary tumors

This article has been updated

Abstract

Pituitary adenomas may hypersecrete hormones (including prolactin, growth hormone and adrenocorticotropic hormone, and rarely follicle-stimulating hormone, luteinizing hormone or TSH) or may be nonfunctional. Despite their high prevalence in the general population, these tumors are invariably benign and exhibit features of differentiated pituitary cell function as well as premature proliferative arrest. Pathogenesis of dysregulated pituitary cell proliferation and unrestrained hormone hypersecretion may be mediated by hypothalamic, intrapituitary and/or peripheral factors. Altered expression of pituitary cell cycle genes, activation of pituitary selective oncoproteins or loss of pituitary suppressor factors may be associated with aberrant growth factor signaling. Considerable information on the etiology of these tumors has been derived from transgenic animal models, which may not accurately and universally reflect human tumor pathophysiology. Understanding subcellular mechanisms that underlie pituitary tumorigenesis will enable development of tumor aggression markers as well as novel targeted therapies.

Key Points

  • Pituitary cell growth and hormone synthesis are controlled by hypothalamic, intrapituitary and peripheral factors

  • Pituitary tumors arising from differentiated hormone-expressing cells are commonly encountered and are invariably benign

  • Adenomas may secrete one or more hormones including prolactin, growth hormone, adrenocorticotropic hormone, glycoprotein gonadotroph subunits or hormones, or TSH; most are nonsecreting with no obvious peripheral clinical phenotype

  • The pathogenetic mechanisms that underlie pituitary tumorigenesis may be genetic or epigenetic and result in cell cycle dysregulation, signaling defects or loss of tumor suppressor factors

  • Rarely, patients present with pituitary tumors that are components of familial genetic syndromes

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Cascade of pituitary tumorigenesis.
Figure 2: Intracellular signaling associated with pituitary cell proliferation and transformation.

Change history

  • 01 April 2011

    In the version of this article initially published online, there was an error in the penultimate sentence of page 4. This sentence should have read 'Pttg was isolated from rat pituitary tumor cells by differential RNA display with normal pituitary glands, and is also induced by the E2F transcription factor in the pituitary gland.45,46' The error has been corrected for the print, HTML and PDF versions of the article.

References

  1. Melmed, S. Mechanisms for pituitary tumorigenesis: the plastic pituitary. J. Clin. Invest. 112, 1603–1618 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Levy, A. & Lightman, S. Molecular defects in the pathogenesis of pituitary tumours. Front. Neuroendocrinol. 24, 94–127 (2003).

    CAS  PubMed  Google Scholar 

  3. Scully, K. M. & Rosenfeld, M. G. Pituitary development: regulatory codes in mammalian organogenesis. Science 295, 2231–2235 (2002).

    CAS  PubMed  Google Scholar 

  4. Keegan, C. E. & Camper, S. A. Mouse knockout solves endocrine puzzle and promotes new pituitary lineage model. Genes Dev. 17, 677–682 (2003).

    CAS  Google Scholar 

  5. Drouin, J. Molecular mechanisms of pituitary differentiation and regulation: implications for hormone deficiencies and hormone resistance syndromes. Front. Horm. Res. 35, 74–87 (2006).

    CAS  PubMed  Google Scholar 

  6. Mehta, A. & Dattani, M. T. Developmental disorders of the hypothalamus and pituitary gland associated with congential hypopituitarism. Best Pract. Res. Clin. Endocrinol. Metab. 22, 191–206 (2007).

    Google Scholar 

  7. Li, X., Perissi, V., Liu, F., Rose, D. W. & Rosenfeld, M. G. Tissue-specific regulation of retinal and pituitary precursor cell proliferation. Science 297, 1180–1183 (2002).

    CAS  PubMed  Google Scholar 

  8. Romero, C. J., Nesi-Franca, S. & Radovick, S. The molecular basis of hypopituitarism. Trends Endocrinol. Metab. 20, 506–516 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Moons, D. S. et al. Pituitary hypoplasia and lactotroph dysfunction in mice deficient for cyclin-dependent kinase-4. Endocrinology 143, 3001–3008 (2002).

    CAS  PubMed  Google Scholar 

  10. Wang, Z., Yu, R. & Melmed, S. Mice lacking pituitary tumor transforming gene show testicular and splenic hypoplasia, thymic hyperplasia, thrombocytopenia, aberrant cell cycle progression, and premature centromere division. Mol. Endocrinol. 15, 1870–1879 (2001).

    CAS  PubMed  Google Scholar 

  11. Al-Gahtany, M., Horvath, E. & Kovacs, K. Pituitary hyperplasia. Hormones (Athens) 2, 149–158 (2003).

    Google Scholar 

  12. Ben-Jonathan, N. & Liu, J. W. Pituitary lactotrophs: endocrine, paracrine, juxtacrine, and autocrine interactions. Trends Endocrinol. Metab. 3, 254–258 (1992).

    CAS  PubMed  Google Scholar 

  13. Heaney, A. P., Horwitz, G. A., Wang, Z., Singson, R. & Melmed, S. Early involvement of estrogen-induced pituitary tumor transforming gene and fibroblast growth factor expression in prolactinoma pathogenesis. Nat. Med. 5, 1317–1321 (1999).

    CAS  PubMed  Google Scholar 

  14. Alkhani, A. M. et al. Cytology of pituitary thyrotroph hyperplasia in protracted primary hypothyroidism. Pituitary 1, 291–295 (1999).

    CAS  PubMed  Google Scholar 

  15. Herman, V., Fagin, J., Gonsky, R., Kovacs, K. & Melmed, S. Clonal origin of pituitary adenomas. J. Clin. Endocrinol. Metab. 71, 1427–1433 (1990).

    CAS  PubMed  Google Scholar 

  16. Gleiberman, A. S. et al. Genetic approaches identify adult pituitary stem cells. Proc. Natl Acad. Sci. USA 105, 6332–6337 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Fauquier, T., Rizzoti, K., Dattani, M., Lovell-Badge, R. & Robinson, I. C. SOX2-expressing progenitor cells generate all of the major cell types in the adult mouse pituitary gland. Proc. Natl Acad. Sci. USA 105, 2907–2912 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Hosoyama, T. et al. A postnatal pax7 progenitor gives rise to pituitary adenomas. Genes Cancer 1, 388–402 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Fernandez, A., Karavitaki, N. & Wass, J. A. Prevalence of pituitary adenomas: a community-based, cross-sectional study in Banbury (Oxfordshire, UK). Clin. Endocrinol. (Oxf.) 72, 377–382 (2010).

    Google Scholar 

  20. Daly, A. F. et al. High prevalence of pituitary adenomas: a cross-sectional study in the province of Liege, Belgium. J. Clin. Endocrinol. Metab. 91, 4769–4775 (2006).

    CAS  PubMed  Google Scholar 

  21. Raappana, A., Koivukangas, J., Ebeling, T. & Pirila, T. Incidence of pituitary adenomas in Northern Finland in 1992–2007. J. Clin. Endocrinol. Metab. 95, 4268–4275 (2010).

    CAS  PubMed  Google Scholar 

  22. Kovacs, K., Horvath, E. & Vidal, S. Classification of pituitary adenomas. J. Neurooncol. 54, 121–127 (2001).

    CAS  PubMed  Google Scholar 

  23. Al-Brahim, N. Y. & Asa, S. L. My approach to pathology of the pituitary gland. J. Clin. Pathol. 59, 1245–1253 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Cooper, O. et al. Silent corticogonadotroph adenomas: clinical and cellular characteristics and long-term outcomes. Horm. Cancer 1, 80–92 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Ben-Shlomo, A. & Melmed, S. Pituitary somatostatin receptor signaling. Trends Endocrinol. Metab. 21, 123–133 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Melmed, S. Acromegaly pathogenesis and treatment. J. Clin. Invest. 119, 3189–3202 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Jacks, T. et al. Effects of an Rb mutation in the mouse. Nature 359, 295–300 (1992).

    CAS  PubMed  Google Scholar 

  28. Kiyokawa, H. et al. Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27(Kip1). Cell 85, 721–732 (1996).

    Article  CAS  PubMed  Google Scholar 

  29. Abbud, R. A. et al. Early multipotential pituitary focal hyperplasia in the alpha-subunit of glycoprotein hormone-driven pituitary tumor-transforming gene transgenic mice. Mol. Endocrinol. 19, 1383–1391 (2005).

    CAS  PubMed  Google Scholar 

  30. Ewing, I. et al. A mutation and expression analysis of the oncogene BRAF in pituitary adenomas. Clin. Endocrinol. (Oxf.) 66, 348–352 (2007).

    CAS  Google Scholar 

  31. Asa, S. L. & Ezzat, S. The pathogenesis of pituitary tumors. Annu. Rev. Pathol. 4, 97–126 (2009).

    CAS  PubMed  Google Scholar 

  32. Galland, F. et al. Differential gene expression profiles of invasive and non-invasive non-functioning pituitary adenomas based on microarray analysis. Endocr. Relat. Cancer 17, 361–371 (2010).

    CAS  Google Scholar 

  33. Moreno, C. S. et al. Novel molecular signaling and classification of human clinically nonfunctional pituitary adenomas identified by gene expression profiling and proteomic analyses. Cancer Res. 65, 10214–10222 (2005).

    CAS  PubMed  Google Scholar 

  34. Zhan, X. & Desiderio, D. M. Signaling pathway networks mined from human pituitary adenoma proteomics data. BMC Med. Genomics 3, 13 (2010).

    PubMed  PubMed Central  Google Scholar 

  35. Tanase, C. P., Neagu, M. & Albulescu, R. Key signaling molecules in pituitary tumors. Expert Rev. Mol. Diagn. 9, 859–877 (2009).

    PubMed  Google Scholar 

  36. Attwooll, C., Lazzerini Denchi, E. & Helin, K. The E2F family: specific functions and overlapping interests. EMBO J. 23, 4709–4716 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Lazzerini Denchi, E., Attwooll, C., Pasini, D. & Helin, K. Deregulated E2F activity induces hyperplasia and senescence-like features in the mouse pituitary gland. Mol. Cell Biol. 25, 2660–2672 (2005).

    PubMed  Google Scholar 

  38. Simpson, D. J., Hibberts, N. A., McNicol, A. M., Clayton, R. N. & Farrell, W. E. Loss of pRb expression in pituitary adenomas is associated with methylation of the RB1 CpG island. Cancer Res. 60, 1211–1216 (2000).

    CAS  PubMed  Google Scholar 

  39. Simpson, D. J. et al. Molecular pathology shows p16 methylation in nonadenomatous pituitaries from patients with Cushing's disease. Clin. Cancer Res. 10, 1780–1788 (2004).

    CAS  PubMed  Google Scholar 

  40. Hossain, M. G. et al. Expression of p18(INK4C) is down-regulated in human pituitary adenomas. Endocr. Pathol. 20, 114–121 (2009).

    CAS  PubMed  Google Scholar 

  41. Roussel-Gervais, A. et al. Cooperation between Cyclin E and p27(Kip1) in pituitary tumorigenesis. Mol. Endocrinol. 24, 1835–1845 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Alexandraki, K. I. & Grossman, A. B. Novel insights in the diagnosis of Cushing's syndrome. Neuroendocrinology 92 (Suppl. 1), 35–43 (2010).

    CAS  PubMed  Google Scholar 

  43. Bilodeau, S. et al. Role of Brg1 and HDAC2 in GR trans-repression of the pituitary POMC gene and misexpression in Cushing disease. Genes Dev. 20, 2871–2886 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Bellodi, C. et al. Loss of function of the tumor suppressor DKC1 perturbs p27 translation control and contributes to pituitary tumorigenesis. Cancer Res. 70, 6026–6035 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Pei, L. & Melmed, S. Isolation and characterization of a pituitary tumor-transforming gene (PTTG). Mol. Endocrinol. 11, 433–441 (1997).

    CAS  PubMed  Google Scholar 

  46. Zhou, C., Wawrowsky, K., Bannykh, S., Gutman, S. & Melmed, S. E2F1 induces pituitary tumor transforming gene (PTTG1) expression in human pituitary tumors. Mol. Endocrinol. 23, 2000–2012 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Zou, H., McGarry, T. J., Bernal, T. & Kirschner, M. W. Identification of a vertebrate sister-chromatid separation inhibitor involved in transformation and tumorigenesis. Science 285, 418–422 (1999).

    CAS  PubMed  Google Scholar 

  48. Yu, R., Lu, W., Chen, J., McCabe, C. J. & Melmed, S. Overexpressed pituitary tumor-transforming gene causes aneuploidy in live human cells. Endocrinology 144, 4991–4998 (2003).

    CAS  PubMed  Google Scholar 

  49. Yu, R., Heaney, A. P., Lu, W., Chen, J. & Melmed, S. Pituitary tumor transforming gene causes aneuploidy and p53-dependent and p53-independent apoptosis. J. Biol. Chem. 275, 36502–36505 (2000).

    CAS  PubMed  Google Scholar 

  50. Bernal, J. A. et al. Proliferative potential after DNA damage and non-homologous end joining are affected by loss of securin. Cell Death Differ. 15, 202–212 (2008).

    CAS  PubMed  Google Scholar 

  51. Kim, D. S. et al. Securin induces genetic instability in colorectal cancer by inhibiting double-stranded DNA repair activity. Carcinogenesis 28, 749–759 (2007).

    CAS  PubMed  Google Scholar 

  52. Kim, D. et al. Pituitary tumour transforming gene (PTTG) induces genetic instability in thyroid cells. Oncogene 24, 4861–4866 (2005).

    CAS  PubMed  Google Scholar 

  53. Hayward, B. E. et al. Imprinting of the G(s)alpha gene GNAS1 in the pathogenesis of acromegaly. J. Clin. Invest. 107, R31–R36 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Landis, C. A. et al. GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature 340, 692–696 (1989).

    CAS  PubMed  Google Scholar 

  55. Landis, C. A. et al. Clinical characteristics of acromegalic patients whose pituitary tumors contain mutant Gs protein. J. Clin. Endocrinol. Metab. 71, 1416–1420 (1990).

    CAS  PubMed  Google Scholar 

  56. 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).

    CAS  PubMed  Google Scholar 

  57. Weinstein, L. S. et al. Activating mutations of the stimulatory G. protein in the McCune–Albright syndrome. N. Engl. J. Med. 325, 1688–1695 (1991).

    CAS  PubMed  Google Scholar 

  58. Lania, A. G. et al. Evolution of an aggressive prolactinoma into a growth hormone secreting pituitary tumor coincident with GNAS gene mutation. J. Clin. Endocrinol. Metab. 95, 13–17 (2010).

    CAS  PubMed  Google Scholar 

  59. Ezzat, S., Zheng, L., Zhu, X. F., Wu, G. E. & Asa, S. L. Targeted expression of a human pituitary tumor-derived isoform of FGF receptor-4 recapitulates pituitary tumorigenesis. J. Clin. Invest. 109, 69–78 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Theodoropoulou, M. et al. Expression of epidermal growth factor receptor in neoplastic pituitary cells: evidence for a role in corticotropinoma cells. J. Endocrinol. 183, 385–394 (2004).

    CAS  PubMed  Google Scholar 

  61. Vlotides, G. et al. Heregulin regulates prolactinoma gene expression. Cancer Res. 69, 4209–4216 (2009).

    CAS  Google Scholar 

  62. Missale, C. et al. Nerve growth factor suppresses the transforming phenotype of human prolactinomas. Proc. Natl Acad. Sci. USA 90, 7961–7965 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Shorts-Cary, L. et al. Bone morphogenetic protein and retinoic acid-inducible neural specific protein-3 is expressed in gonadotrope cell pituitary adenomas and induces proliferation, migration, and invasion. Endocrinology 148, 967–975 (2007).

    CAS  PubMed  Google Scholar 

  64. Onofri, C. et al. Localization of vascular endothelial growth factor (VEGF) receptors in normal and adenomatous pituitaries: detection of a non-endothelial function of VEGF in pituitary tumours. J. Endocrinol. 191, 249–261 (2006).

    CAS  PubMed  Google Scholar 

  65. Dworakowska, D. et al. 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 (2009).

    CAS  PubMed  Google Scholar 

  66. Elston, M. S. et al. Wnt pathway inhibitors are strongly down-regulated in pituitary tumors. Endocrinology 149, 1235–1242 (2008).

    CAS  PubMed  Google Scholar 

  67. Miyakoshi, T. et al. Expression of Wnt4 in human pituitary adenomas regulates activation of the beta-catenin-independent pathway. Endocr. Pathol. 19, 261–273 (2008).

    CAS  PubMed  Google Scholar 

  68. Fan, X. et al. Gonadotropin-positive pituitary tumors accompanied by ovarian tumors in aging female ERbeta-/- mice. Proc. Natl Acad. Sci. USA 107, 6453–6458 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Manoranjan, B. et al. Estrogen receptors alpha and beta immunohistochemical expression: clinicopathological correlations in pituitary adenomas. Anticancer Res. 30, 2897–2904 (2010).

    CAS  PubMed  Google Scholar 

  70. Ezzat, S. Epigenetic control in pituitary tumors. Endocr. J. 55, 951–957 (2008).

    CAS  PubMed  Google Scholar 

  71. Rubinek, T. et al. The cell adhesion molecules N-cadherin and neural cell adhesion molecule regulate human growth hormone: a novel mechanism for regulating pituitary hormone secretion. J. Clin. Endocrinol. Metab. 88, 3724–3730 (2003).

    CAS  PubMed  Google Scholar 

  72. Paez-Pereda, M. et al. Involvement of bone morphogenetic protein 4 (BMP-4) in pituitary prolactinoma pathogenesis through a Smad/estrogen receptor crosstalk. Proc. Natl Acad. Sci. USA 100, 1034–1039 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Jin, L. et al. Transforming growth factor-beta, transforming growth factor-beta receptor II, and p27Kip1 expression in nontumorous and neoplastic human pituitaries. Am. J. Pathol. 151, 509–519 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Auernhammer, C. J. & Melmed, S. Leukemia-inhibitory factor-neuroimmune modulator of endocrine function. Endocr. Rev. 21, 313–345 (2000).

    CAS  PubMed  Google Scholar 

  75. Arzt, E. gp130 cytokine signaling in the pituitary gland: a paradigm for cytokine-neuro-endocrine pathways. J. Clin. Invest. 108, 1729–1733 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Fedele, M. et al. Overexpression of the HMGA2 gene in transgenic mice leads to the onset of pituitary adenomas. Oncogene 21, 3190–3198 (2002).

    CAS  PubMed  Google Scholar 

  77. Fedele, M. et al. HMGA2 induces pituitary tumorigenesis by enhancing E2F1 activity. Cancer Cell 9, 459–471 (2006).

    CAS  PubMed  Google Scholar 

  78. Qian, Z. R. et al. Overexpression of HMGA2 relates to reduction of the let-7 and its relationship to clinicopathological features in pituitary adenomas. Mod. Pathol. 22, 431–441 (2009).

    CAS  PubMed  Google Scholar 

  79. De Martino, I. et al. HMGA proteins up-regulate CCNB2 gene in mouse and human pituitary adenomas. Cancer Res. 69, 1844–1850 (2009).

    CAS  PubMed  Google Scholar 

  80. Dudley, K. J., Revill, K., Whitby, P., Clayton, R. N. & Farrell, W. E. Genome-wide analysis in a murine Dnmt1 knockdown model identifies epigenetically silenced genes in primary human pituitary tumors. Mol. Cancer Res. 6, 1567–1574 (2008).

    CAS  PubMed  Google Scholar 

  81. Zhang, H. Y. et al. RUNX1 and RUNX2 upregulate Galectin-3 expression in human pituitary tumors. Endocrine 35, 101–111 (2009).

    CAS  PubMed  Google Scholar 

  82. Pagotto, U. et al. The expression of the antiproliferative gene ZAC is lost or highly reduced in nonfunctioning pituitary adenomas. Cancer Res. 60, 6794–6799 (2000).

    CAS  PubMed  Google Scholar 

  83. Theodoropoulou, M. et al. Tumor ZAC1 expression is associated with the response to somatostatin analog therapy in patients with acromegaly. Int. J. Cancer 125, 2122–2126 (2009).

    CAS  PubMed  Google Scholar 

  84. Zhang, X. et al. Loss of expression of GADD45 gamma, a growth inhibitory gene, in human pituitary adenomas: implications for tumorigenesis. J. Clin. Endocrinol. Metab. 87, 1262–1267 (2002).

    CAS  PubMed  Google Scholar 

  85. Zhang, X. et al. Maternally expressed gene 3 (MEG3) noncoding ribonucleic acid: isoform structure, expression, and functions. Endocrinology 151, 939–947 (2010).

    CAS  PubMed  Google Scholar 

  86. Ezzat, S., Yu, S. & Asa, S. L. The zinc finger Ikaros transcription factor regulates pituitary growth hormone and prolactin gene expression through distinct effects on chromatin accessibility. Mol. Endocrinol. 19, 1004–1011 (2005).

    CAS  PubMed  Google Scholar 

  87. Ezzat, S. et al. Ikaros integrates endocrine and immune system development. J. Clin. Invest. 115, 1021–1029 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Revill, K., Dudley, K. J., Clayton, R. N., McNicol, A. M. & Farrell, W. E. Loss of neuronatin expression is associated with promoter hypermethylation in pituitary adenoma. Endocr. Relat. Cancer 16, 537–548 (2009).

    CAS  PubMed  Google Scholar 

  89. Fusco, A. MicroRNAs: a great challenge for the diagnosis and therapy of endocrine cancers. Endocr. Relat. Cancer 17, E3–E4 (2010).

    PubMed  Google Scholar 

  90. Amaral, F. C. et al. MicroRNAs differentially expressed in ACTH-secreting pituitary tumors. J. Clin. Endocrinol. Metab. 94, 320–323 (2009).

    CAS  PubMed  Google Scholar 

  91. Stilling, G. et al. MicroRNA expression in ACTH-producing pituitary tumors: up-regulation of microRNA-122 and -493 in pituitary carcinomas. Endocrine 38, 67–75 (2010).

    CAS  PubMed  Google Scholar 

  92. Bottoni, A. et al. Identification of differentially expressed microRNAs by microarray: a possible role for microRNA genes in pituitary adenomas. J. Cell Physiol. 210, 370–377 (2007).

    CAS  PubMed  Google Scholar 

  93. Butz, H. et al. Down-regulation of Wee1 kinase by a specific subset of microRNA in human sporadic pituitary adenomas. J. Clin. Endocrinol. Metab. 95, E181–E191 (2010).

    CAS  PubMed  Google Scholar 

  94. Elston, M. S., McDonald, K. L., Clifton-Bligh, R. J. & Robinson, B. G. Familial pituitary tumor syndromes. Nat. Rev. Endocrinol. 5, 453–461 (2009).

    CAS  PubMed  Google Scholar 

  95. Marx, S. J. et al. Multiple endocrine neoplasia type 1: clinical and genetic features of the hereditary endocrine neoplasias. Recent Prog. Horm. Res. 54, 397–438 (1999).

    CAS  PubMed  Google Scholar 

  96. Pellegata, N. S. et al. Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc. Natl Acad. Sci. USA 103, 15558–15563 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Igreja, S. et al. Assessment of p27 (cyclin-dependent kinase inhibitor 1B) and aryl hydrocarbon receptor-interacting protein (AIP) genes in multiple endocrine neoplasia (MEN1) syndrome patients without any detectable MEN1 gene mutations. Clin. Endocrinol. (Oxf.) 70, 259–264 (2009).

    CAS  Google Scholar 

  98. Georgitsi, M. et al. Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia. J. Clin. Endocrinol. Metab. 92, 3321–3325 (2007).

    CAS  PubMed  Google Scholar 

  99. Molatore, S. & Pellegata, N. S. The MENX syndrome and p27: relationships with multiple endocrine neoplasia. Prog. Brain Res. 182, 295–320 (2010).

    CAS  PubMed  Google Scholar 

  100. Agarwal, S. K., Mateo, C. M. & Marx, S. J. Rare germline mutations in cyclin-dependent kinase inhibitor genes in multiple endocrine neoplasia type 1 and related states. J. Clin. Endocrinol. Metab. 94, 1826–1834 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Boikos, S. A. & Stratakis, C. A. Carney complex: the first 20 years. Curr. Opin. Oncol. 19, 24–29 (2007).

    CAS  PubMed  Google Scholar 

  102. Yin, Z., Williams-Simons, L., Parlow, A. F., Asa, S. & Kirschner, L. S. Pituitary-specific knockout of the Carney complex gene Prkar1a leads to pituitary tumorigenesis. Mol. Endocrinol. 22, 380–387 (2008).

    CAS  PubMed  Google Scholar 

  103. Gadelha, M. R. et al. Loss of heterozygosity on chromosome 11q13 in two families with acromegaly/gigantism is independent of mutations of the multiple endocrine neoplasia type I gene. J. Clin. Endocrinol. Metab. 84, 249–256 (1999).

    CAS  PubMed  Google Scholar 

  104. Georgitsi, M. et al. Molecular diagnosis of pituitary adenoma predisposition caused by aryl hydrocarbon receptor-interacting protein gene mutations. Proc. Natl Acad. Sci. USA 104, 4101–4105 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Vierimaa, O. et al. Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Science 312, 1228–1230 (2006).

    CAS  PubMed  Google Scholar 

  106. Daly, A. F. et al. Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families. J. Clin. Endocrinol. Metab. 92, 1891–1896 (2007).

    CAS  PubMed  Google Scholar 

  107. Leontiou, C. A. et al. The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas. J. Clin. Endocrinol. Metab. 93, 2390–2401 (2008).

    CAS  PubMed  Google Scholar 

  108. Georgitsi, M. et al. Large genomic deletions in AIP in pituitary adenoma predisposition. J. Clin. Endocrinol. Metab. 93, 4146–4151 (2008).

    CAS  PubMed  Google Scholar 

  109. Vargiolu, M. et al. The tyrosine kinase receptor RET interacts in vivo with aryl hydrocarbon receptor-interacting protein to alter survivin availability. J. Clin. Endocrinol. Metab. 94, 2571–2578 (2009).

    CAS  PubMed  Google Scholar 

  110. Raitila, A. et al. Mice with inactivation of aryl hydrocarbon receptor-interacting protein (Aip) display complete penetrance of pituitary adenomas with aberrant ARNT expression. Am. J. Pathol. 177, 1969–1976 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Heliovaara, E. et al. The expression of AIP-related molecules in elucidation of cellular pathways in pituitary adenomas. Am. J. Pathol. 175, 2501–2507 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Chahal, H. S., Chapple, J. P., Frohman, L. A., Grossman, A. B. & Korbonits, M. Clinical, genetic and molecular characterization of patients with familial isolated pituitary adenomas (FIPA). Trends Endocrinol. Metab. 21, 419–427 (2010).

    CAS  PubMed  Google Scholar 

  113. Farrell, W. E. Pituitary tumours: findings from whole genome analyses. Endocr. Relat. Cancer 13, 707–716 (2006).

    CAS  PubMed  Google Scholar 

  114. Farrell, W. E. & Clayton, R. N. Epigenetic change in pituitary tumorigenesis. Endocr. Relat. Cancer 10, 323–330 (2003).

    CAS  PubMed  Google Scholar 

  115. Sharpless, N. E. & DePinho, R. A. Telomeres, stem cells, senescence, and cancer. J. Clin. Invest. 113, 160–168 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Schmitt, C. A. et al. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 109, 335–346 (2002).

    CAS  PubMed  Google Scholar 

  117. Campisi, J. Suppressing cancer: the importance of being senescent. Science 309, 886–887 (2005).

    CAS  PubMed  Google Scholar 

  118. Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997).

    CAS  PubMed  Google Scholar 

  119. Bartkova, J. et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633–637 (2006).

    CAS  PubMed  Google Scholar 

  120. Vlotides, G., Eigler, T. & Melmed, S. Pituitary tumor-transforming gene: physiology and implications for tumorigenesis. Endocr. Rev. 28, 165–186 (2007).

    CAS  PubMed  Google Scholar 

  121. Chesnokova, V., Kovacs, K., Castro, A. V., Zonis, S. & Melmed, S. Pituitary hypoplasia in Pttg−/− mice is protective for Rb+/− pituitary tumorigenesis. Mol. Endocrinol. 19, 2371–2379 (2005).

    CAS  PubMed  Google Scholar 

  122. Chesnokova, V. et al. Senescence mediates pituitary hypoplasia and restrains pituitary tumor growth. Cancer Res. 67, 10564–10572 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Uccella, S. et al. Aneuploidy, centrosome alteration and securin overexpression as features of pituitary somatotroph and lactotroph adenomas. Anal. Quant. Cytol. Histol. 27, 241–252 (2005).

    PubMed  Google Scholar 

  124. Chesnokova, V. et al. p21(Cip1) restrains pituitary tumor growth. Proc. Natl Acad. Sci. USA 105, 17498–17503 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Fukuoka, H. et al. HER2/ErbB2 receptor signaling in rat and human prolactinoma cells: strategy for targeted prolactinoma therapy. Mol. Endocrinol. 25, 92–103 (2011).

    CAS  PubMed  Google Scholar 

  126. Fougner, S. L. et al. The expression of E-cadherin in somatotroph pituitary adenomas is related to tumor size, invasiveness, and somatostatin analog response. J. Clin. Endocrinol. Metab. 95, 2334–2342 (2010).

    CAS  PubMed  Google Scholar 

  127. Pertuit, M., Barlier, A., Enjalbert, A. & Gerard, C. Signalling pathway alterations in pituitary adenomas: involvement of Gsalpha, cAMP and mitogen-activated protein kinases. J. Neuroendocrinol. 21, 869–877 (2009).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Melmed, S. Pathogenesis of pituitary tumors. Nat Rev Endocrinol 7, 257–266 (2011). https://doi.org/10.1038/nrendo.2011.40

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2011.40

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing