Lkb1 deficiency causes prostate neoplasia in the mouse.
Mutation of LKB1 is the key molecular event underlying Peutz-Jeghers syndrome, a dominantly inherited condition characterized by a predisposition to a range of malignancies, including those of the reproductive system. We report here the use of a Cre-LoxP strategy to directly address the role of Lkb1 in prostate neoplasia. Recombination of a LoxP-flanked Lkb1 allele within all four murine prostate lobes was mediated by spontaneous activation of a p450 CYP1A1-driven Cre recombinase transgene (termed AhCre). Homozygous mutation of Lkb1 in males expressing AhCre reduced longevity, with 100% manifesting atypical hyperplasia and 83% developing prostate intraepithelial neoplasia (PIN) of the anterior prostate within 2 to 4 months. We also observed focal hyperplasia of the dorsolateral and ventral lobes (61% and 56% incidence, respectively), bulbourethral gland cysts associated with atypical hyperplasia (100% incidence), hyperplasia of the urethra (39% incidence), and seminal vesicle squamous metaplasia (11% incidence). PIN foci overexpressed nuclear beta-catenin, p-Gsk3 beta, and downstream Wnt targets. Immunohistochemical analysis of foci also showed a reduction in Pten activation and up-regulation of both p-PDK1 (an AMPK kinase) and phosphorylated Akt. Our data are therefore consistent with deregulation of Wnt and phosphoinositide 3-kinase/Akt signaling cascades after loss of Lkb1 function. For the first time, this model establishes a link between the tumor suppressor Lkb1 and prostate neoplasia, highlighting a tumor suppressive role within the mouse and raising the possibility of a similar association in the human.
Pearson
Helen B
HB
Cardiff University, School of Biosciences, Cardiff, Wales, United Kingdom.
McCarthy
Afshan
A
Collins
Christopher M P
CM
Ashworth
Alan
A
Clarke
Alan R
AR
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000818:Animals; D019426:Integrases / Q000235:genetics; D008297:Male; D051379:Mice; D051058:Oncogene Protein v-akt / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics; D011995:Recombination, Genetic; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D019076:Transgenes
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D019426:Integrases; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C491654:Stk11 protein, mouse; C045073:Cre recombinase; C487757:Pten protein, mouse