Endometrial cancer is the most common gynecologic cancer in the United States. Multiple studies suggest that dysregulated miRNA molecules play a role in endometrial cancer. To study this, the Hawkins lab used conditional genetically engineered mouse models to delete DICER, a key enzyme in miRNA biogenesis, (PgrCre; Dicerf/f). These mice had significantly dysregulated miRNA expression and infertility but did not develop endometrial cancer. The most common gene defect in endometrial cancer is functional loss of the tumor suppressor, PTEN.
Conditional deletion of Pten in the mouse uterus (PgrCre; Ptenf/f) leads to low-grade endometrioid adenocarcinoma of the uterus. Women with low-grade endometrioid tumors do well clinically. However, women with high-grade tumors have poor five-year survival. Additionally, therapies that are effective against these aggressive tumors are unknown. Combination of loss of Dicer and loss of Pten leads to aggressive high-grade clear cell endometrial cancers in the mice. Future studies will focus on steroid hormone effects, the role of specific miRNA molecules in aggressive tumors and the role of uterine stem cells. Additional studies developing genetically similar in vitro models using CRISPR/Cas9 will be used.