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Lkb1 defiency causes prostate neoplasia in the mouse

Pearson, Helen B., McCarthy, A., Collins, C. M., Ashworth, A. and Clarke, Alan Richard 2008. Lkb1 defiency causes prostate neoplasia in the mouse. Cancer Research 68 (7) , pp. 2223-2232. 10.1158/0008-5472.CAN-07-5169

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Abstract

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 β-catenin, p-Gsk3β, 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. [Cancer Res 2008;68(7):2223–32]

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
ISSN: 0008-5472
Last Modified: 03 Apr 2019 11:40
URI: http://orca-mwe.cf.ac.uk/id/eprint/9056

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