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LKB1 Deficiency Sensitizes Mice to Carcinogen-Induced Tumorigenesis

¹ Massachusetts General Hospital, Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts and ² Department of Pathology, University of Vermont, Burlington, Vermont

Requests for reprints: Nabeel Bardeesy, Massachusetts General Hospital Cancer Center, CPZN 4216, Cancer Center, Simches Research Building, Boston, MA 02114. Phone: 617-643-2579; E-mail: Bardeesy.Nabeel{at}MGH.Harvard.edu.

Lkb1 is a central regulator of cell polarity and energy metabolism through its capacity to activate the AMP-activated protein kinase (AMPK)–related family of protein kinases. Germ line–inactivating mutation of Lkb1 leads to Peutz-Jeghers syndrome, which is characterized by benign hamartomas and a susceptibility to malignant epithelial tumors. Mutations in Lkb1 are also found in sporadic carcinomas, most frequently in lung cancers associated with tobacco carcinogen exposure. The basis for Lkb1-dependent tumor suppression is not defined. Here, we uncover a marked sensitivity of Lkb1 mutant mice to the chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). Lkb1^+/– mice are highly prone to DMBA-induced squamous cell carcinoma (SCC) of the skin and lung. Confirming a cell autonomous tumor suppressor role of Lkb1, mice with epidermal-specific Lkb1 deletion are also susceptible to DMBA-induced SCC and develop spontaneous SCC with long latency. Restoration of wild-type Lkb1 causes senescence in tumor-derived cell lines, a process that can be partially bypassed by inactivation of the Rb pathway, but not by inactivation of p53 or AMPK. Our data indicate that Lkb1 is a potent suppressor of carcinogen-induced skin and lung cancers and that downstream targets beyond the AMPK-mTOR pathway are likely mediators of Lkb1-dependent tumor suppression. [Cancer Res 2008;68(1):55–63]

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				Correction: Carcinogen-Induced Tumors in Lkb1 Mutant Mice Cancer Res., April 1, 2008; 68(7): 2549 - 2549. [Full Text] [PDF]