LKB1 as a Tumor Suppressor in Uterine Cancer: Mouse Models and Translational Studies

Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 943)

Abstract

The LKB1 tumor suppressor was identified in 1998 as the gene mutated in the Peutz–Jeghers Syndrome (PJS), a hereditary cancer predisposition characterized by gastrointestinal polyposis and a high incidence of cancers, particularly carcinomas, at a variety of anatomic sites including the gastrointestinal tract, lung, and female reproductive tract. Women with PJS have a high incidence of carcinomas of the uterine corpus (endometrium) and cervix. The LKB1 gene is also somatically mutated in human cancers arising at these sites. Work in mouse models has highlighted the potency of LKB1 as an endometrial tumor suppressor and its distinctive roles in driving invasive and metastatic growth. These in vivo models represent tractable experimental systems for the discovery of underlying biological principles and molecular processes regulated by LKB1 in the context of tumorigenesis and also serve as useful preclinical model systems for experimental therapeutics. Here we review LKB1’s known roles in mTOR signaling, metabolism, and cell polarity, with an emphasis on human pathology and mouse models relevant to uterine carcinogenesis, including cancers of the uterine corpus and cervix.

Keywords

LKB1 STK11 Endometrial cancer Uterine cancer Genetically engineered mouse models MTOR AMPK Therapeutics 

References

  1. 1.
    Hemminki A, et al. Localization of a susceptibility locus for Peutz-Jeghers syndrome to 19p using comparative genomic hybridization and targeted linkage analysis. Nat Genet. 1997;15(1):87–90.PubMedGoogle Scholar
  2. 2.
    Sanchez-Cespedes M. A role for LKB1 gene in human cancer beyond the Peutz-Jeghers syndrome. Oncogene. 2007;26(57):7825–32.PubMedGoogle Scholar
  3. 3.
    Hemminki A, et al. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature. 1998;391(6663):184–7.PubMedGoogle Scholar
  4. 4.
    Mehenni H, et al. Loss of LKB1 kinase activity in Peutz-Jeghers syndrome, and evidence for allelic and locus heterogeneity. Am J Hum Genet. 1998;63(6):1641–50.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Hezel AF, Bardeesy N. LKB1; linking cell structure and tumor suppression. Oncogene. 2008;27(55):6908–19.PubMedGoogle Scholar
  6. 6.
    Beggs AD, et al. Peutz-Jeghers syndrome: a systematic review and recommendations for management. Gut. 2010;59(7):975–86.PubMedGoogle Scholar
  7. 7.
    Wang ZJ, et al. Allelic imbalance at the LKB1 (STK11) locus in tumours from patients with Peutz-Jeghers’ syndrome provides evidence for a hamartoma-(adenoma)-carcinoma sequence. J Pathol. 1999;188(1):9–13.PubMedGoogle Scholar
  8. 8.
    Miyaki M, et al. Somatic mutations of LKB1 and beta-catenin genes in gastrointestinal polyps from patients with Peutz-Jeghers syndrome. Cancer Res. 2000;60(22):6311–3.PubMedGoogle Scholar
  9. 9.
    Entius MM, et al. Molecular genetic alterations in hamartomatous polyps and carcinomas of patients with Peutz-Jeghers syndrome. J Clin Pathol. 2001;54(2):126–31.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Hearle N, et al. Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res. 2006;12(10):3209–15.PubMedGoogle Scholar
  11. 11.
    Giardiello FM, et al. Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology. 2000;119(6):1447–53.PubMedGoogle Scholar
  12. 12.
    Lee SM, et al. Genetic and epigenetic alterations of the LKB1 gene and their associations with mutations in TP53 and EGFR pathway genes in Korean non-small cell lung cancers. Lung Cancer. 2013;81(2):194–9.PubMedGoogle Scholar
  13. 13.
    Esteller M, et al. Epigenetic inactivation of LKB1 in primary tumors associated with the Peutz-Jeghers syndrome. Oncogene. 2000;19(1):164–8.PubMedGoogle Scholar
  14. 14.
    Trojan J, et al. 5'-CpG island methylation of the LKB1/STK11 promoter and allelic loss at chromosome 19p13.3 in sporadic colorectal cancer. Gut. 2000;47(2):272–6.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Genest DR, Dorfman DM, Castrillon DH. Ploidy and imprinting in hydatidiform moles. Complementary use of flow cytometry and immunohistochemistry of the imprinted gene product p57KIP2 to assist molar classification. J Reprod Med. 2002;47(5):342–6.PubMedGoogle Scholar
  16. 16.
    Lu KH, et al. Loss of tuberous sclerosis complex-2 function and activation of mammalian target of rapamycin signaling in endometrial carcinoma. Clin Cancer Res. 2008;14(9):2543–50.PubMedGoogle Scholar
  17. 17.
    Contreras CM, et al. Loss of Lkb1 provokes highly invasive endometrial adenocarcinomas. Cancer Res. 2008;68(3):759–66.PubMedGoogle Scholar
  18. 18.
    Contreras CM, et al. Lkb1 inactivation is sufficient to drive endometrial cancers that are aggressive yet highly responsive to mTOR inhibitor monotherapy. Dis Model Mech. 2010;3(3-4):181–93.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Cancer Genome Atlas Research Network, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67–73.Google Scholar
  20. 20.
    Tanwar PS, et al. Stromal liver kinase B1 [STK11] signaling loss induces oviductal adenomas and endometrial cancer by activating mammalian Target of Rapamycin Complex 1. PLoS Genet. 2012;8(8). e1002906.Google Scholar
  21. 21.
    Cheng H, et al. A genetic mouse model of invasive endometrial cancer driven by concurrent loss of Pten and Lkb1 Is highly responsive to mTOR inhibition. Cancer Res. 2014;74(1):15–23.PubMedGoogle Scholar
  22. 22.
    Gurumurthy S, et al. The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature. 2010;468(7324):659–63.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Nakada D, Saunders TL, Morrison SJ. Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature. 2010;468(7324):653–8.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Gan B, et al. Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells. Nature. 2010;468(7324):701–4.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Katajisto P, et al. LKB1 signaling in mesenchymal cells required for suppression of gastrointestinal polyposis. Nat Genet. 2008;40:455–9.PubMedGoogle Scholar
  26. 26.
    Lim W, et al. Relative frequency and morphology of cancers in STK11 mutation carriers. Gastroenterology. 2004;126(7):1788–94.PubMedGoogle Scholar
  27. 27.
    Resta N, et al. Cancer risk associated with STK11/LKB1 germline mutations in Peutz-Jeghers syndrome patients: results of an Italian multicenter study. Dig Liver Dis. 2013;45(7):606–11.PubMedGoogle Scholar
  28. 28.
    Young RH, Clement PB. Endocervical adenocarcinoma and its variants: their morphology and differential diagnosis. Histopathology. 2002;41(3):185–207.PubMedGoogle Scholar
  29. 29.
    Mikami Y, et al. Gastrointestinal immunophenotype in adenocarcinomas of the uterine cervix and related glandular lesions: a possible link between lobular endocervical glandular hyperplasia/pyloric gland metaplasia and ‘adenoma malignum’. Mod Pathol. 2004;17(8):962–72.PubMedGoogle Scholar
  30. 30.
    Xu JY, et al. Absence of human papillomavirus infection in minimal deviation adenocarcinoma and lobular endocervical glandular hyperplasia. Int J Gynecol Pathol. 2005;24(3):296–302.PubMedGoogle Scholar
  31. 31.
    Wingo SN, et al. Somatic LKB1 mutations promote cervical cancer progression. PLoS One. 2009;4(4):e5137.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Hahn HS, et al. Lobular endocervical glandular hyperplasia in a woman with Peutz-Jeghers syndrome: a case report. Eur J Obstet Gynecol Reprod Biol. 2012;160(1):117–8.PubMedGoogle Scholar
  33. 33.
    Kato N, et al. Pyloric gland metaplasia/differentiation in multiple organ systems in a patient with Peutz-Jegher’s syndrome. Pathol Int. 2011;61(6):369–72.PubMedGoogle Scholar
  34. 34.
    Nucci MR. Pseudoneoplastic glandular lesions of the uterine cervix: a selective review. Int J Gynecol Pathol. 2014;33(4):330–8.PubMedGoogle Scholar
  35. 35.
    Mikami Y, McCluggage WG. Endocervical glandular lesions exhibiting gastric differentiation: an emerging spectrum of benign, premalignant, and malignant lesions. Adv Anat Pathol. 2013;20(4):227–37.PubMedGoogle Scholar
  36. 36.
    Kawauchi S, et al. Is lobular endocervical glandular hyperplasia a cancerous precursor of minimal deviation adenocarcinoma? A comparative molecular-genetic and immunohistochemical study. Am J Surg Pathol. 2008;32(12):1807–15.PubMedGoogle Scholar
  37. 37.
    Nakada Y, et al. The LKB1 tumor suppressor as a biomarker in mouse and human tissues. PLoS One. 2013;8(9):e73449.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Landry D, et al. Endometrioid adenocarcinoma of the uterus with a minimal deviation invasive pattern. Histopathology. 2003;42(1):77–82.PubMedGoogle Scholar
  39. 39.
    Longacre TA, Hendrickson MR. Diffusely infiltrative endometrial adenocarcinoma: an adenoma malignum pattern of myoinvasion. Am J Surg Pathol. 1999;23(1):69–78.PubMedGoogle Scholar
  40. 40.
    Young RH, et al. Ovarian sex cord tumor with annular tubules: review of 74 cases including 27 with Peutz-Jeghers syndrome and four with adenoma malignum of the cervix. Cancer. 1982;50(7):1384–402.PubMedGoogle Scholar
  41. 41.
    Srivatsa PJ, Keeney GL, Podratz KC. Disseminated cervical adenoma malignum and bilateral ovarian sex cord tumors with annular tubules associated with Peutz-Jeghers syndrome. Gynecol Oncol. 1994;53(2):256–64.PubMedGoogle Scholar
  42. 42.
    Buchet-Poyau K, et al. Search for the second Peutz-Jeghers syndrome locus: exclusion of the STK13, PRKCG, KLK10, and PSCD2 genes on chromosome 19 and the STK11IP gene on chromosome 2. Cytogenet Genome Res. 2002;97(3–4):171–8.PubMedGoogle Scholar
  43. 43.
    Mehenni H, et al. Peutz-Jeghers syndrome: confirmation of linkage to chromosome 19p13.3 and identification of a potential second locus, on 19q13.4. Am J Hum Genet. 1997;61(6):1327–34.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Chow E, et al. An updated mutation spectrum in an Australian series of PJS patients provides further evidence for only one gene locus. Clin Genet. 2006;70(5):409–14.PubMedGoogle Scholar
  45. 45.
    Volikos E, et al. LKB1 exonic and whole gene deletions are a common cause of Peutz-Jeghers syndrome. J Med Genet. 2006;43(5):e18.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Vaahtomeri K, Makela TP. Molecular mechanisms of tumor suppression by LKB1. FEBS Lett. 2011;585(7):944–51.PubMedGoogle Scholar
  47. 47.
    Hezel AF, et al. Pancreatic LKB1 deletion leads to acinar polarity defects and cystic neoplasms. Mol Cell Biol. 2008;28(7):2414–25.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Sapkota GP, et al. Ionizing radiation induces ataxia telangiectasia mutated kinase (ATM)-mediated phosphorylation of LKB1/STK11 at Thr-366. Biochem J. 2002;368(Pt 2):507–16.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Alessi DR, Sakamoto K, Bayascas JR. Lkb1-dependent signaling pathways. Annu Rev Biochem. 2006;75:137–63.PubMedGoogle Scholar
  50. 50.
    Xie Z, et al. Phosphorylation of LKB1 at serine 428 by protein kinase C-zeta is required for metformin-enhanced activation of the AMP-activated protein kinase in endothelial cells. Circulation. 2008;117(7):952–62.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Zhu H, et al. Phosphorylation of serine 399 in LKB1 protein short form by protein kinase Czeta is required for its nucleocytoplasmic transport and consequent AMP-activated protein kinase (AMPK) activation. J Biol Chem. 2013;288(23):16495–505.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Song P, et al. Reactive nitrogen species induced by hyperglycemia suppresses Akt signaling and triggers apoptosis by upregulating phosphatase PTEN (phosphatase and tensin homologue deleted on chromosome 10) in an LKB1-dependent manner. Circulation. 2007;116(14):1585–95.PubMedGoogle Scholar
  53. 53.
    Sapkota GP, et al. Identification and characterization of four novel phosphorylation sites (Ser31, Ser325, Thr336 and Thr366) on LKB1/STK11, the protein kinase mutated in Peutz-Jeghers cancer syndrome. Biochem J. 2002;362(Pt 2):481–90.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Sapkota GP, et al. Phosphorylation of the protein kinase mutated in Peutz-Jeghers cancer syndrome, LKB1/STK11, at Ser431 by p90(RSK) and cAMP-dependent protein kinase, but not its farnesylation at Cys(433), is essential for LKB1 to suppress cell vrowth. J Biol Chem. 2001;276(22):19469–82.PubMedGoogle Scholar
  55. 55.
    Collins SP, et al. LKB1, a novel serine/threonine protein kinase and potential tumour suppressor, is phosphorylated by cAMP-dependent protein kinase (PKA) and prenylated in vivo. Biochem J. 2000;345(Pt 3):673–80.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Zeqiraj E, et al. Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation. Science. 2009;326(5960):1707–11.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Milburn CC, et al. Crystal structure of MO25 alpha in complex with the C terminus of the pseudo kinase STE20-related adaptor. Nat Struct Mol Biol. 2004;11(2):193–200.PubMedGoogle Scholar
  58. 58.
    Baas AF, et al. Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD. EMBO J. 2003;22(12):3062–72.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Boudeau J, et al. MO25alpha/beta interact with STRADalpha/beta enhancing their ability to bind, activate and localize LKB1 in the cytoplasm. EMBO J. 2003;22(19):5102–14.PubMedPubMedCentralGoogle Scholar
  60. 60.
    de Leng WW, et al. STRAD in Peutz-Jeghers syndrome and sporadic cancers. J Clin Pathol. 2005;58(10):1091–5.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Alhopuro P, et al. Mutation analysis of three genes encoding novel LKB1-interacting proteins, BRG1, STRADalpha, and MO25alpha, in Peutz-Jeghers syndrome. Br J Cancer. 2005;92(6):1126–9.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Nony P, et al. Stability of the Peutz-Jeghers syndrome kinase LKB1 requires its binding to the molecular chaperones Hsp90/Cdc37. Oncogene. 2003;22(57):9165–75.PubMedGoogle Scholar
  63. 63.
    Gaude H, et al. Molecular chaperone complexes with antagonizing activities regulate stability and activity of the tumor suppressor LKB1. Oncogene. 2012;31(12):1582–91.PubMedGoogle Scholar
  64. 64.
    Hardie DG, et al. Management of cellular energy by the AMP-activated protein kinase system. FEBS Lett. 2003;546(1):113–20.PubMedGoogle Scholar
  65. 65.
    Carling D, Zammit VA, Hardie DG. A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis. FEBS Lett. 1987;223(2):217–22.PubMedGoogle Scholar
  66. 66.
    Hardie DG. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol. 2007;8(10):774–85.PubMedGoogle Scholar
  67. 67.
    Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;115(5):577–90.PubMedGoogle Scholar
  68. 68.
    Gwinn DM, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008;30(2):214–26.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Shamji AF, Nghiem P, Schreiber SL. Integration of growth factor and nutrient signaling: implications for cancer biology. Mol Cell. 2003;12(2):271–80.PubMedGoogle Scholar
  70. 70.
    Baker MD, et al. The small GTPase Rheb is required for spermatogenesis but not oogenesis. Reproduction. 2014;147(5):615–25.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Goncharova EA, et al. Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). J Biol Chem. 2002;277(34):30958–67.PubMedGoogle Scholar
  72. 72.
    Woods A, et al. Characterization of AMP-activated protein kinase beta and gamma subunits. Assembly of the heterotrimeric complex in vitro. J Biol Chem. 1996;271(17):10282–90.PubMedGoogle Scholar
  73. 73.
    Scott JW, et al. CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations. J Clin Invest. 2004;113(2):274–84.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Nath N, McCartney RR, Schmidt MC. Yeast Pak1 kinase associates with and activates Snf1. Mol Cell Biol. 2003;23(11):3909–17.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Sutherland CM, et al. Elm1p is one of three upstream kinases for the Saccharomyces cerevisiae SNF1 complex. Curr Biol. 2003;13(15):1299–305.PubMedGoogle Scholar
  76. 76.
    Hong SP, et al. Activation of yeast Snf1 and mammalian AMP-activated protein kinase by upstream kinases. Proc Natl Acad Sci U S A. 2003;100(15):8839–43.PubMedPubMedCentralGoogle Scholar
  77. 77.
    Hawley SA, et al. Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol. 2003;2(4):28.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Woods A, et al. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr Biol. 2003;13(22):2004–8.PubMedGoogle Scholar
  79. 79.
    Lizcano JM, et al. LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J. 2004;23(4):833–43.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Zagorska A, et al. New roles for the LKB1-NUAK pathway in controlling myosin phosphatase complexes and cell adhesion. Sci Signal. 2010;3(115):ra25.PubMedGoogle Scholar
  81. 81.
    Courchet J, et al. Terminal axon branching is regulated by the LKB1-NUAK1 kinase pathway via presynaptic mitochondrial capture. Cell. 2013;153(7):1510–25.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Chan KT, et al. LKB1 loss in melanoma disrupts directional migration toward extracellular matrix cues. J Cell Biol. 2014;207(2):299–315.PubMedPubMedCentralGoogle Scholar
  83. 83.
    Watts JL, et al. The C. elegans par-4 gene encodes a putative serine-threonine kinase required for establishing embryonic asymmetry. Development. 2000;127(7):1467–75.PubMedGoogle Scholar
  84. 84.
    Martin SG, Johnston DS. A role for Drosophila LKB1 in anterior-posterior axis formation and epithelial polarity. Nature. 2003;421(6921):379–84.PubMedGoogle Scholar
  85. 85.
    Szczepanska K, Maleszewski M. LKB1/PAR4 protein is asymmetrically localized in mouse oocytes and associates with meiotic spindle. Gene Expr Patterns. 2005;6(1):86–93.PubMedGoogle Scholar
  86. 86.
    Zheng B, Cantley LC. Regulation of epithelial tight junction assembly and disassembly by AMP-activated protein kinase. Proc Natl Acad Sci U S A. 2007;104(3):819–22.PubMedPubMedCentralGoogle Scholar
  87. 87.
    Zhang L, et al. AMP-activated protein kinase regulates the assembly of epithelial tight junctions. Proc Natl Acad Sci U S A. 2006;103(46):17272–7.PubMedPubMedCentralGoogle Scholar
  88. 88.
    Tanwar PS, et al. Altered LKB1/AMPK/TSC1/TSC2/mTOR signaling causes disruption of Sertoli cell polarity and spermatogenesis. Hum Mol Genet. 2012;21(20):4394–405.PubMedPubMedCentralGoogle Scholar
  89. 89.
    Barnes AP, et al. LKB1 and SAD kinases define a pathway required for the polarization of cortical neurons. Cell. 2007;129(3):549–63.PubMedGoogle Scholar
  90. 90.
    Amin N, et al. LKB1 regulates polarity remodeling and adherens junction formation in the Drosophila eye. Proc Natl Acad Sci U S A. 2009;106(22):8941–6.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Pease JC, Tirnauer JS. Mitotic spindle misorientation in cancer--out of alignment and into the fire. J Cell Sci. 2011;124(Pt 7):1007–16.PubMedGoogle Scholar
  92. 92.
    Partanen JI, et al. Tumor suppressor function of Liver kinase B1 (Lkb1) is linked to regulation of epithelial integrity. Proc Natl Acad Sci U S A. 2012;109(7):E388–97.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Royer C, Lu X. Epithelial cell polarity: a major gatekeeper against cancer? Cell Death Differ. 2011;18(9):1470–7.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Muschler J, Streuli CH. Cell-matrix interactions in mammary gland development and breast cancer. Cold Spring Harb Perspect Biol. 2010;2(10):a003202.PubMedPubMedCentralGoogle Scholar
  95. 95.
    Baas AF, et al. Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD. Cell. 2004;116(3):457–66.PubMedGoogle Scholar
  96. 96.
    Eggers CM, et al. STE20-related kinase adaptor protein alpha (STRADalpha) regulates cell polarity and invasion through PAK1 signaling in LKB1-null cells. J Biol Chem. 2012;287(22):18758–68.PubMedPubMedCentralGoogle Scholar
  97. 97.
    Shaw RJ, et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell. 2004;6(1):91–9.PubMedGoogle Scholar
  98. 98.
    Shaw RJ, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005;310(5754):1642–6.PubMedPubMedCentralGoogle Scholar
  99. 99.
    Andrade-Vieira R, et al. Loss of LKB1 expression reduces the latency of ErbB2-mediated mammary gland tumorigenesis, promoting changes in metabolic pathways. PLoS One. 2013;8(2):e56567.PubMedPubMedCentralGoogle Scholar
  100. 100.
    Shaw RJ, et al. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci U S A. 2004;101(10):3329–35.PubMedPubMedCentralGoogle Scholar
  101. 101.
    Bardeesy N, et al. Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. Nature. 2002;419(6903):162–7.PubMedGoogle Scholar
  102. 102.
    Kato K, et al. Critical roles of AMP-activated protein kinase in constitutive tolerance of cancer cells to nutrient deprivation and tumor formation. Oncogene. 2002;21(39):6082–90.PubMedGoogle Scholar
  103. 103.
    Liang J, et al. The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat Cell Biol. 2007;9(2):218–24.PubMedGoogle Scholar
  104. 104.
    Sanchez-Cespedes M, et al. Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res. 2002;62(13):3659–62.PubMedGoogle Scholar
  105. 105.
    Faubert B, et al. Loss of the tumor suppressor LKB1 promotes metabolic reprogramming of cancer cells via HIF-1alpha. Proc Natl Acad Sci U S A. 2014;111(7):2554–9.PubMedPubMedCentralGoogle Scholar
  106. 106.
    Faubert B, et al. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab. 2013;17(1):113–24.PubMedGoogle Scholar
  107. 107.
    Gao Y, et al. LKB1 inhibits lung cancer progression through lysyl oxidase and extracellular matrix remodeling. Proc Natl Acad Sci U S A. 2010;107(44):18892–7.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Gera JF, et al. AKT activity determines sensitivity to mammalian target of rapamycin (mTOR) inhibitors by regulating cyclin D1 and c-myc expression. J Biol Chem. 2004;279(4):2737–46.PubMedGoogle Scholar
  109. 109.
    Porstmann T, et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 2008;8(3):224–36.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Grabiner BC, et al. A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity. Cancer Discov. 2014;4(5):554–63.PubMedPubMedCentralGoogle Scholar
  111. 111.
    Wagle N, et al. Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib. Cancer Discov. 2014;4(5):546–53.PubMedPubMedCentralGoogle Scholar
  112. 112.
    Alvarez EA, et al. Phase II trial of combination bevacizumab and temsirolimus in the treatment of recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2013;129(1):22–7.PubMedGoogle Scholar
  113. 113.
    Mackay HJ, et al. Molecular determinants of outcome with mammalian target of rapamycin inhibition in endometrial cancer. Cancer. 2014;120(4):603–10.PubMedGoogle Scholar
  114. 114.
    Nucci MR, et al. Biomarkers in diagnostic obstetric and gynecologic pathology: a review. Adv Anat Pathol. 2003;10(2):55–68.PubMedGoogle Scholar
  115. 115.
    Komiya T, et al. Enhanced activity of the CREB co-activator Crtc1 in LKB1 null lung cancer. Oncogene. 2010;29(11):1672–80.PubMedGoogle Scholar
  116. 116.
    Cao C, et al. Role of LKB1-CRTC1 on glycosylated COX-2 and response to COX-2 inhibition in lung cancer. J Natl Cancer Inst. 2015;107(1):358.PubMedGoogle Scholar
  117. 117.
    Greer EL, et al. An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans. Curr Biol. 2007;17(19):1646–56.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Tsai LH, et al. The MZF1/c-MYC axis mediates lung adenocarcinoma progression caused by wild-type lkb1 loss. Oncogene. 2015;34(13):1641–9.PubMedGoogle Scholar
  119. 119.
    Jacob LS, et al. Genome-wide RNAi screen reveals disease-associated genes that are common to Hedgehog and Wnt signaling. Sci Signal. 2011;4(157):ra4.PubMedPubMedCentralGoogle Scholar
  120. 120.
    Conkright MD, et al. TORCs: transducers of regulated CREB activity. Mol Cell. 2003;12(2):413–23.PubMedGoogle Scholar
  121. 121.
    Iourgenko V, et al. Identification of a family of cAMP response element-binding protein coactivators by genome-scale functional analysis in mammalian cells. Proc Natl Acad Sci U S A. 2003;100(21):12147–52.PubMedPubMedCentralGoogle Scholar
  122. 122.
    Altarejos JY, Montminy M. CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nat Rev Mol Cell Biol. 2011;12(3):141–51.PubMedPubMedCentralGoogle Scholar
  123. 123.
    Feng Y, et al. The CRTC1-NEDD9 signaling axis mediates lung cancer progression caused by LKB1 loss. Cancer Res. 2012;72(24):6502–11.PubMedPubMedCentralGoogle Scholar
  124. 124.
    Gu Y, et al. Altered LKB1/CREB-regulated transcription co-activator (CRTC) signaling axis promotes esophageal cancer cell migration and invasion. Oncogene. 2012;31(4):469–79.PubMedGoogle Scholar
  125. 125.
    Koo SH, et al. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature. 2005;437(7062):1109–11.PubMedGoogle Scholar
  126. 126.
    Katoh Y, et al. Silencing the constitutive active transcription factor CREB by the LKB1-SIK signaling cascade. FEBS J. 2006;273(12):2730–48.PubMedGoogle Scholar
  127. 127.
    Clark K, et al. Phosphorylation of CRTC3 by the salt-inducible kinases controls the interconversion of classically activated and regulatory macrophages. Proc Natl Acad Sci U S A. 2012;109(42):16986–91.PubMedPubMedCentralGoogle Scholar
  128. 128.
    Catalano S, et al. Evidence that leptin through STAT and CREB signaling enhances cyclin D1 expression and promotes human endometrial cancer proliferation. J Cell Physiol. 2009;218(3):490–500.PubMedGoogle Scholar
  129. 129.
    Casaburi I, et al. Chenodeoxycholic acid through a TGR5-dependent CREB signaling activation enhances cyclin D1 expression and promotes human endometrial cancer cell proliferation. Cell Cycle. 2012;11(14):2699–710.PubMedGoogle Scholar
  130. 130.
    O’Connor T, Borsig L, Heikenwalder M. CCL2-CCR2 signaling in disease pathogenesis. Endocr Metab Immune Disord Drug Targets. 2015;15(2):105–18.PubMedGoogle Scholar
  131. 131.
    Pena CG, et al. LKB1 loss promotes endometrial cancer progression via CCL2-dependent macrophage recruitment. J Clin Invest. 2015;125(11):4063–76.PubMedPubMedCentralGoogle Scholar
  132. 132.
    Corsini M, et al. Cyclic adenosine monophosphate-response element-binding protein mediates the proangiogenic or proinflammatory activity of gremlin. Arterioscler Thromb Vasc Biol. 2014;34(1):136–45.PubMedGoogle Scholar
  133. 133.
    Dje N'Guessan P, et al. Statins control oxidized LDL-mediated histone modifications and gene expression in cultured human endothelial cells. Arterioscler Thromb Vasc Biol. 2009;29(3):380–6.PubMedGoogle Scholar
  134. 134.
    Armaiz-Pena GN, et al. Adrenergic regulation of monocyte chemotactic protein 1 leads to enhanced macrophage recruitment and ovarian carcinoma growth. Oncotarget. 2014;6(6):4266–73.PubMedCentralGoogle Scholar
  135. 135.
    Brown KA, et al. LKB1 expression is inhibited by estradiol-17beta in MCF-7 cells. J Steroid Biochem Mol Biol. 2011;127(3-5):439–43.PubMedGoogle Scholar
  136. 136.
    Linher-Melville K, Singh G. The transcriptional responsiveness of LKB1 to STAT-mediated signaling is differentially modulated by prolactin in human breast cancer cells. BMC Cancer. 2014;14:415.PubMedPubMedCentralGoogle Scholar
  137. 137.
    Co NN, et al. Loss of LKB1 in high-grade endometrial carcinoma: LKB1 is a novel transcriptional target of p53. Cancer. 2014;120(22):3457–68.PubMedPubMedCentralGoogle Scholar
  138. 138.
    Linher-Melville K, Zantinge S, Singh G. Liver kinase B1 expression (LKB1) is repressed by estrogen receptor alpha (ERalpha) in MCF-7 human breast cancer cells. Biochem Biophys Res Commun. 2012;417(3):1063–8.PubMedGoogle Scholar
  139. 139.
    Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol. 1983;15(1):10–7.PubMedGoogle Scholar
  140. 140.
    Tashiro H, et al. p53 gene mutations are common in uterine serous carcinoma and occur early in their pathogenesis. Am J Pathol. 1997;150(1):177–85.PubMedPubMedCentralGoogle Scholar
  141. 141.
    Qanungo S, Haldar S, Basu A. Restoration of silenced Peutz-Jeghers syndrome gene, LKB1, induces apoptosis in pancreatic carcinoma cells. Neoplasia. 2003;5(4):367–74.PubMedPubMedCentralGoogle Scholar
  142. 142.
    Ylikorkala A, et al. Vascular abnormalities and deregulation of VEGF in Lkb1-deficient mice. Science. 2001;293(5533):1323–6.PubMedGoogle Scholar
  143. 143.
    Miyoshi H, et al. Gastrointestinal hamartomatous polyposis in Lkb1 heterozygous knockout mice. Cancer Res. 2002;62(8):2261–6.PubMedGoogle Scholar
  144. 144.
    Jishage K, et al. Role of Lkb1, the causative gene of Peutz-Jegher’s syndrome, in embryogenesis and polyposis. Proc Natl Acad Sci U S A. 2002;99(13):8903–8.PubMedPubMedCentralGoogle Scholar
  145. 145.
    Korsse SE, et al. Identification of molecular alterations in gastrointestinal carcinomas and dysplastic hamartomas in Peutz-Jeghers syndrome. Carcinogenesis. 2013;34(7):1611–9.PubMedGoogle Scholar
  146. 146.
    Ollila S, Makela TP. The tumor suppressor kinase LKB1: lessons from mouse models. J Mol Cell Biol. 2011;3(6):330–40.PubMedGoogle Scholar
  147. 147.
    McCarthy A, et al. Conditional deletion of the Lkb1 gene in the mouse mammary gland induces tumour formation. J Pathol. 2009;219(3):306–16.PubMedGoogle Scholar
  148. 148.
    Xu C, et al. Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression. Cancer Cell. 2014;25(5):590–604.PubMedPubMedCentralGoogle Scholar
  149. 149.
    Liu W, et al. LKB1/STK11 inactivation leads to expansion of a prometastatic tumor subpopulation in melanoma. Cancer Cell. 2012;21(6):751–64.PubMedPubMedCentralGoogle Scholar
  150. 150.
    Beauparlant SL, Read PW, Di Cristofano A. In vivo adenovirus-mediated gene transduction into mouse endometrial glands: a novel tool to model endometrial cancer in the mouse. Gynecol Oncol. 2004;94(3):713–8.PubMedGoogle Scholar
  151. 151.
    Gallardo TD, et al. Genomewide discovery and classification of candidate ovarian fertility genes in the mouse. Genetics. 2007;177(1):179–94.PubMedPubMedCentralGoogle Scholar
  152. 152.
    Barakat RR, et al. Corpus: epithelial tumors. In: Hoskins WJ, Perez CA, Young RC, editors. Principles and practice of gynecologic oncology. 3rd ed. Philadelphia: Lippincott Williams and Wilkins; 2000. p. 921–59.Google Scholar
  153. 153.
    Susini T, et al. Ten-year results of a prospective study on the prognostic role of ploidy in endometrial carcinoma: dNA aneuploidy identifies high-risk cases among the so-called ‘low-risk’ patients with well and moderately differentiated tumors. Cancer. 2007;109(5):882–90.PubMedGoogle Scholar
  154. 154.
    Akbay EA, et al. Cooperation between p53 and the telomere-protecting shelterin component Pot1a in endometrial carcinogenesis. Oncogene. 2013;32(17):2211–9.PubMedGoogle Scholar
  155. 155.
    Frese KK, Tuveson DA. Maximizing mouse cancer models. Nat Rev Cancer. 2007;7(9):645–58.PubMedGoogle Scholar
  156. 156.
    Shackelford DB, et al. mTOR and HIF-1{alpha}-mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome. Proc Natl Acad Sci U S A. 2009;106(27):11137–42.PubMedPubMedCentralGoogle Scholar
  157. 157.
    Ojesina AI, et al. Landscape of genomic alterations in cervical carcinomas. Nature. 2014;506(7488):371–5.PubMedGoogle Scholar
  158. 158.
    Hu Z, et al. TALEN-mediated targeting of HPV oncogenes ameliorates HPV-related cervical malignancy. J Clin Invest. 2015;125(1):425–36.PubMedGoogle Scholar
  159. 159.
    Chung SH, Lambert PF. Prevention and treatment of cervical cancer in mice using estrogen receptor antagonists. Proc Natl Acad Sci U S A. 2009;106(46):19467–72.PubMedPubMedCentralGoogle Scholar
  160. 160.
    Nakau M, et al. Hepatocellular carcinoma caused by loss of heterozygosity in Lkb1 gene knockout mice. Cancer Res. 2002;62(16):4549–53.PubMedGoogle Scholar
  161. 161.
    Takeda H, et al. Accelerated onsets of gastric hamartomas and hepatic adenomas/carcinomas in Lkb1+/-p53-/- compound mutant mice. Oncogene. 2006;25(12):1816–20.PubMedGoogle Scholar
  162. 162.
    Hobbs RM, et al. Distinct germline progenitor subsets defined through Tsc2-mTORC1 signaling. EMBO Rep. 2015;16(4):467–80.PubMedPubMedCentralGoogle Scholar
  163. 163.
    Morton JP, et al. LKB1 haploinsufficiency cooperates with Kras to promote pancreatic cancer through suppression of p21-dependent growth arrest. Gastroenterology. 2010;139(2):586–97. 597 e1–6.PubMedPubMedCentralGoogle Scholar
  164. 164.
    Huang X, et al. Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem J. 2008;412(2):211–21.PubMedGoogle Scholar
  165. 165.
    Wei C, et al. Mutation of Lkb1 and p53 genes exert a cooperative effect on tumorigenesis. Cancer Res. 2005;65(24):11297–303.PubMedGoogle Scholar
  166. 166.
    Yang QE, et al. Retinoblastoma protein (RB1) controls fate determination in stem cells and progenitors of the mouse male germline. Biol Reprod. 2013;89(5):113.PubMedPubMedCentralGoogle Scholar
  167. 167.
    Pearson HB, et al. Lkb1 deficiency causes prostate neoplasia in the mouse. Cancer Res. 2008;68(7):2223–32.PubMedGoogle Scholar
  168. 168.
    Ji H, et al. LKB1 modulates lung cancer differentiation and metastasis. Nature. 2007;448(7155):807–10.PubMedGoogle Scholar
  169. 169.
    Gurumurthy S, et al. LKB1 deficiency sensitizes mice to carcinogen-induced tumorigenesis. Cancer Res. 2008;68(1):55–63.PubMedPubMedCentralGoogle Scholar
  170. 170.
    Robinson J, et al. Osteogenic tumours in Lkb1-deficient mice. Exp Mol Pathol. 2008;85(3):223–6.PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of Cell Systems and AnatomyUT Health Science Center at San AntonioSan AntonioUSA
  2. 2.Department of PathologyUT Southwestern Medical CenterDallasUSA

Personalised recommendations