title: LKB1 haploinsufficiency cooperates with Kras to promote pancreatic cancer through suppression of p21-dependent growth arrest.
abstract: OBJECTIVE
  Patients carrying germline mutations of LKB1 have an increased risk of pancreatic cancer; however, it is unclear whether down-regulation of LKB1 is an important event in sporadic pancreatic cancer. In this study, we aimed to investigate the impact of LKB1 down-regulation for pancreatic cancer in mouse and human and to elucidate the mechanism by which Lkb1 deregulation contributes to this disease.
  
  
  METHODS
  We first investigated the consequences of Lkb1 deficiency in a genetically modified mouse model of pancreatic cancer, both in terms of disease progression and at the molecular level. To test the relevance of our findings to human pancreatic cancer, we investigated levels of LKB1 and its potential targets in human pancreatic cancer.
  
  
  RESULTS
  We definitively show that Lkb1 haploinsufficiency can cooperate with oncogenic KrasG12D to cause pancreatic ductal adenocarcinoma (PDAC) in the mouse. Mechanistically, this was associated with decreased p53/p21-dependent growth arrest. Haploinsufficiency for p21 (Cdkn1a) also synergizes with KrasG12D to drive PDAC in the mouse. We also found that levels of LKB1 expression were decreased in around 20% of human PDAC and significantly correlated with low levels of p21 and a poor prognosis. Remarkably, all tumors that had low levels of LKB1 had low levels of p21, and these tumors did not express mutant p53.
  
  
  CONCLUSIONS
  We have identified a novel LKB1-p21 axis that suppresses PDAC following Kras mutation in vivo. Down-regulation of LKB1 may therefore serve as an alternative to p53 mutation to drive pancreatic cancer in vivo.
authors.affiliation: Beatson Institute for Cancer Research, Garscube Estate, Glasgow, UK.
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Morton
authors.forename: Nigel B
authors.initials: NB
authors.lastname: Jamieson
authors.forename: Saadia A
authors.initials: SA
authors.lastname: Karim
authors.forename: Dimitris
authors.initials: D
authors.lastname: Athineos
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Ridgway
authors.forename: Colin
authors.initials: C
authors.lastname: Nixon
authors.forename: Colin J
authors.initials: CJ
authors.lastname: McKay
authors.forename: Ross
authors.initials: R
authors.lastname: Carter
authors.forename: Valerie G
authors.initials: VG
authors.lastname: Brunton
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Frame
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.forename: Karin A
authors.initials: KA
authors.lastname: Oien
authors.forename: T R Jeffry
authors.initials: TR
authors.lastname: Evans
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D016147:Genes, Tumor Suppressor; D005838:Genotype; D006239:Haplotypes; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics; D006720:Homozygote; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D010641:Phenotype; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018570:Risk Assessment; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018398:Homeodomain Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; C084010:pancreatic and duodenal homeobox 1 protein; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C491654:Stk11 protein, mouse; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
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