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Mutation of Lkb1 and p53 Genes Exert a Cooperative Effect on Tumorigenesis

Departments of ¹ Epidemiology, ² Veterinary Medicine and Surgery, ³ Molecular Genetics, and ⁴ Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Marsha L. Frazier, Department of Epidemiology, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-3393; Fax: 713-563-0999; E-mail: mlfrazier{at}mail.mdanderson.org.

Peutz-Jeghers syndrome (PJS) is a dominantly inherited disorder characterized by gastrointestinal hamartomatous polyps and mucocutaneous melanin pigmentation. Germ line mutations in LKB1 cause PJS. We have generated mice carrying an Lkb1 exon 2 to 8 deletion by gene targeting in embryonic stem cells. Heterozygotes develop gastric hamartomas that are histologically similar to those found in humans with PJS. LKB1 is also reportedly a mediator of p53-dependent apoptosis. To explore the potential combined effects of p53 and Lkb1 alterations on tumorigenesis, we carried out a series of matings with Lkb1^+/– and p53 null mice to generate Lkb1^+/–/p53^+/– and Lkb1^+/–/p53^–/– mice. Similar to the Lkb1^+/– mice, gastrointestinal hamartomas have also been detected in the mice with these two genotypes. The Lkb1^+/–/p53^+/– mice displayed a dramatically reduced life span and increased tumor incidence compared to the mice with either Lkb1 or p53 single gene knockout. The time to onset of polyposis in Lkb1^+/–/p53^–/– mice is 2 months earlier than Lkb1^+/–/p53^+/– and Lkb1^+/– mice, whereas the latter two show a similar time to onset which is at 6 months of age. These results strongly suggested that mutations of p53 and Lkb1 gene cooperate in the acceleration of tumorigenesis. (Cancer Res 2005; 65(24): 11297-303)

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