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Lkb1 deficiency causes prostate neoplasia in the mouse
Helen B Pearson1, Afshan McCarthy, Christopher M P Collins
1Cardiff University, School of Biosciences, Cardiff, Wales, United Kingdom.
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 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.
Insights
Loss of the LKB1 tumor suppressor gene in mice leads to prostate cancer development. This study establishes a new mouse model for LKB1-deficient prostate neoplasia, crucial for understanding cancer progression.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Peutz-Jeghers syndrome is linked to LKB1 mutations, increasing cancer risk.
- The role of LKB1 in prostate cancer development is not fully understood.
- A Cre-LoxP system is utilized to investigate LKB1's function in the prostate.
Purpose of the Study:
- To investigate the role of LKB1 in prostate neoplasia using a conditional knockout mouse model.
- To elucidate the molecular pathways affected by LKB1 loss in prostate cancer.
Main Methods:
- A Cre-LoxP strategy was employed to achieve tissue-specific deletion of Lkb1.
- Spontaneous activation of a p450 CYP1A1-driven Cre recombinase transgene (AhCre) mediated recombination.
- Homozygous Lkb1 mutation was induced in the prostate lobes of male mice.
Main Results:
- Lkb1 mutation in mice resulted in reduced longevity, atypical hyperplasia, and prostate intraepithelial neoplasia (PIN).
- Specific prostatic lobes and associated glands showed hyperplastic changes and metaplasia.
- PIN foci exhibited altered expression of beta-catenin, Wnt targets, Pten, and the PI3K/Akt pathway components.
Conclusions:
- Loss of LKB1 function in the prostate leads to deregulation of Wnt and PI3K/Akt signaling.
- This study establishes a novel mouse model linking LKB1 to prostate neoplasia.
- The findings suggest a tumor suppressive role for LKB1 in the prostate, with potential implications for human prostate cancer.
