The Role of LKBI Tumor Suppressor in Endometrial Cancer




Contreras, Cristina Maria

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The LKB1 gene contributes to endometrial carcinogenesis in both the mouse and human. Although this role was not anticipated based on the tumor spectrum observed in Peutz Jegher women, many tumor suppressors have been found to have a much broader role in cancer than would have been predicted on the tumor spectrum associated with the hereditary syndrome. The studies that comprise this dissertation work first demonstrate that in addition to gastrointestinal polyposis, mice heterozygous for LKB1 develop endometrial cancers. To develop a better model of LKB1-driven endometrial carcinogenesis not prone to death from GI obstruction, two model systems were developed based on conditional ablation of the LKB1. In the first, intrauterine delivery of a CRE-expressing adenovirus was employed. A striking 65% of mice in this system, developed highly invasive endometrial tumors by 9 months. Although this system allowed the demonstration and exploration of the role of LKB1 as an endometrial tumor suppressor, the model suffered from technical limitations stemming from its recombination inefficiency. Then, in collaboration, a much more efficient transgenic model was developed using the promoter region of SPRR2F to drive CRE expression specifically in the endometrial epithelium. With this model, female mice with homozygous endometrial LKB1 inactivation developed diffuse malignant transformation of their entire endometrium with rapid extrauterine spread and death, by 7 months, suggesting that LKB1 inactivation was sufficient to promote the development of invasive endometrial cancer. This much improved model also permitted the exploration of theory that LKB1-deficient tumors should be hypersensitive to rapamycin. Collectively these studies demonstrate that LKB1 is a uniquely potent endometrial tumor suppressor but also suggest that clinical responses to mTOR inhibitors may be linked to LKB1 inactivation.

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