The endometrium, the specialized lining of the uterus, is the most common target tissue for cancers of the female reproductive tract. Early-stage endometrial cancers can be cured, but patients diagnosed with late-stage disease have a median survival of less than a year, and the effectiveness of treatment has not improved in the last 30 years. Animal models of endometrial cancer have been developed but, to date, none has solely endometrial-specific expression, a prerequisite for the precisely targeted genetic manipulation that is needed to study the molecular biology of the disease. The tumor suppressor gene LKB1 is frequently mutated in human cancers, and decreased LKB1 expression in endometrial cancer correlates with a higher grade and stage. LKB1 encodes a protein kinase that normally restrains the activation of the AMP-dependent kinase (AMPK)-mammalian target of rapamycin (mTOR) signaling pathway, whose deregulation is important for the initiation and progression of many cancers. Inhibitors of the mTOR protein itself, such as temsirolimus, a rapamycin derivative, have been used to treat renal cell and endometrial cancers, although only a minority of patients respond.

This paper addresses the dual need for the development of a new model system for endometrial cancer and the study of LKB1-driven neoplasia. The authors identify an endometrial-specific promoter and use it to drive expression of Cre recombinase in transgenic mice, meaning that any gene of interest can be manipulated in the endometrial epithelium. They use these mice to explore the consequences of deletion of the mouse Lkb1 gene in endometrial cancer. Aggressive, invasive endometrial cancers with an early onset and 100% incidence developed, resulting in extrauterine tumor spread and death. The effects of loss of Lkb1 were partially reversed by blocking the resulting hyperactivation of the AMPK-mTOR pathway using the mTOR inhibitor rapamycin. Prolonged rapamycin administration not only slowed the growth of early tumors, but also resulted in shrinkage of advanced tumors, and significant clinical remissions.

Lkb1 is a remarkably potent endometrial tumor suppressor, as its inactivation is sufficient to drive the rapid formation of invasive and lethal endometrial cancers. In addition to developing a new model for endometrial cancer, this is the first study demonstrating that rapamycin is an effective agent against invasive cancers that are driven by Lkb1 deficiency. The model described here can be used to further dissect the initiation and progression of endometrial cancer, and the data also provide a rationale for the setup of clinical trials to test the idea that LKB1 deficiency is a sensitive indicator of responsiveness to anticancer therapies using rapamycin analogs.