The role of cholesterol biosynthesis in metastatic and recurrent endometrialcancer

子宫内膜癌是最常见的妇科恶性肿瘤，2021年估计有66，570例新发病例。 虽然早期和低级别子宫内膜癌通常表现出良好的预后，但转移性子宫内膜癌的发生率较高。 并且复发性子宫内膜癌对于大多数妇女来说用目前可用的标准疗法是不可治愈的。 因此，探讨肿瘤转移和复发的机制， 进一步阐明子宫内膜癌的进展。我们培育了一种基因工程老鼠 转移性和复发性子宫内膜癌的模型，涉及Pten和Mig-6突变共存， 子宫内膜癌Pten突变不足以引起远处转移，但同时消融Pten基因的小鼠， Mig-6和Pten发生远处转移。突变小鼠子宫内膜癌I期子宫切除术后 在Pten和Mig-6缺乏的情况下，双突变小鼠在子宫内膜癌中复发。 腹部和肺部我们的初步结果表明，胆固醇相关基因的表达 在突变小鼠中，生物合成途径显著增加。根据这些结果，我们 假设PTEN-6抑制子宫内膜癌转移和复发 通过抑制胆固醇的生物合成而突变。我们的具体目标是为了了解：1） PTEN基因突变的子宫内膜癌复发时，PTEN-6缺失的致瘤作用; 2） 突变小鼠中原发性肿瘤、循环肿瘤细胞和复发性肿瘤的特征;和3） 他汀类药物预防子宫内膜癌复发。我们的假设的新奇有很强的创新性 和尖端的技术方法。特别是，我们将采用第一个临床前动物模型， 与具有远处转移和复发的人子宫内膜癌非常相似。

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.