The role of cholesterol biosynthesis in metastatic and recurrent endometrialcancer

Endometrial cancer is the most common gynecologic malignancy, with an estimated 66,570 new cases in 2021. Although early-stage and low grade endometrial cancer generally exhibits a favorable prognosis, metastatic and recurrent endometrial cancer is incurable with currently available standard therapies for most women. Therefore, there is an urgent obligation to explore the mechanism of tumor metastasis and recurrence to further elucidate the progression of endometrial cancer. We have developed a genetically engineered mouse model for metastatic and recurrent endometrial cancer that implicates coexistent Pten and Mig-6 mutations in endometrial cancer. Pten mutation is not sufficient for distant metastasis, but mice with concurrent ablation of Mig-6 and Pten develop distant metastasis. After hysterectomy at stage I of endometrial cancer in mutant mice with deficiency of Pten and Mig-6, the double mutant mice developed recurrence of endometrial cancer in the abdomen and lung. Our preliminary results show that the expression of genes related to cholesterol biosynthesis pathway was significantly increased in the mutant mice. Based upon these results, we hypothesize that MIG-6 suppresses metastasis and recurrence in endometrial cancer with PTEN mutation by inhibiting cholesterol biosynthesis. Our Specific Aims are directed at understanding: 1) the tumorigenic effects of MIG-6 loss in recurrence of endometrial cancer with PTEN mutation; 2) the molecular signature of primary tumor, circulating tumor cells, and recurrent tumor in the mutant mice; and 3) the ability of statins to prevent recurrence in endometrial cancer. There is strong innovation in the novelty of our hypotheses and cutting-edge technical approaches. In particular, we will employ the first preclinical animal model that closely resembles human endometrial cancer with distant metastasis and recurrence.