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Lkb1 Deficiency Causes Prostate Neoplasia in the Mouse

¹ Cardiff University, School of Biosciences, Cardiff, Wales, United Kingdom; ² Breakthrough Breast Cancer Research Center, The Institute of Cancer Research, London, United Kingdom; and ³ Bristol Royal Infirmary, Department of Pathology, Bristol, United Kingdom

Requests for reprints: Alan Clarke, University of Cardiff, Museum Avenue, Cardiff, South Glamorgan, CF10 3US, United Kingdom. Phone: 44-0-2920-879115; Fax: 44-02920 874116; E-mail: Clarkear{at}cardifff.ac.uk.

Key Words: LKB1 (STK11) • prostate • cancer • Wnt

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]