Metformin for the Chemoprevention of Endometrial Cancer In Obese, Insulin-Resista

肥胖女性患子宫内膜癌的风险明显增加。无数的流行病学 研究表明，肥胖与子宫内膜癌风险的增加密切相关。 普通女性一生患子宫内膜癌的风险为3%，而肥胖女性的终身风险为9%-10% 患子宫内膜癌的风险。在美国癌症研究所对饮食与癌症的评论中 世界癌症研究基金会(WCRF)，作者指出，与体重指数和 子宫内膜癌的发病率最高。而性腺外雌激素(雌酮)的过度产生 在肥胖女性的脂肪组织中被认为是子宫内膜风险的主要贡献者 癌症、血清雌激素水平的升高不太可能完全解释这种影响。我们的研究 研究小组和其他人提出，与肥胖相关的胰岛素抵抗会增加患糖尿病的风险 子宫内膜癌。此外，我们上一个资助期的数据表明，其他机制有 参与肥胖症子宫内膜促增殖信号通路的激活。就目前而言 建议，我们的中心假设是二甲双胍可以减少子宫内膜的过度增殖和 可以作为胰岛素抵抗型肥胖女性的化学预防药物。我们的三个具体目标是1) 验证二甲双胍可逆转雌激素依赖的大鼠卵巢细胞过度增殖的假设 肥胖诱导的胰岛素抵抗动物模型的子宫内膜，2)研究新的机制 与使用二甲双胍预防子宫内膜癌有关。更具体地说，我们将检查 脂肪组织中表达的脂肪因子通过脂肪因子调节子宫内膜增殖的假说 受体，和二甲双胍治疗可以防止这种增殖，以及3)评估二甲双胍的能力 在一组肥胖、胰岛素抵抗的女性中调节替代子宫内膜生物标记物。它的目标是 该项目旨在开发新的策略来化学预防肥胖、胰岛素引起的子宫内膜癌。 抵抗力强的女性是高危人群。

Obese women clearly are at increased risk for developing endometrial cancer. Numerous epidemiologic studies have demonstrated that obesity is strongly associated with an increased risk of endometrial cancer. While an average woman has a 3% lifetime risk of endometrial cancer, obese women have a 9-10% lifetime risk of endometrial cancer. In a review of diet and cancer by the American Institute for Cancer Research and World Cancer Research Fund (WCRF), authors stated that the evidence relating body mass index and cancer is strongest for endometrial cancer. While excessive production of extragonadal estrogens (estrone) in the adipose tissue of obese women is presumed to be the major contributor to the risk of endometrial cancer, increased serum estrogen levels alone are unlikely to fully account for this effect. Studies by our group and others suggest that insulin resistance associated with obesity contributes to the increased risk of endometrial cancer. In addition, data from our previous funding period suggest that other mechanisms are involved in activating pro-proliferative signaling pathways in the obese endometrium. For the current proposal, our central hypothesis is that metformin can decrease endometrial hyperproliferation and can act as a chemopreventive agent in insulin-resistant obese women. Our three specific aims are 1) to test the hypothesis that metformin can reverse the estrogen-dependent hyperproliferation in the endometrium in an animal model of obesity- induced insulin-resistance, 2) to study novel mechanisms related to the use of metformin for the prevention of endometrial cancer. More specifically, we will examine the hypothesis that adipokines expressed in adipose tissue regulate endometrial proliferation via adipokine receptors, and metformin treatment can prevent this proliferation, and 3) to assess the ability of metformin to modulate surrogate endometrial biomarkers in a cohort of obese, insulin resistant women. It is the goal of this Project to develop novel strategies for the chemoprevention of endometrial cancer in obese, insulin resistant women, a high risk cohort.