GENES AND THE ESTROGEN EFFECT ON ENDOMETRIAL CANCER

描述(申请人提供)：子宫内膜癌的病因是 相对较好的理解。雌激素对子宫内膜的刺激作用 孕激素的调节作用是主要原因。雌激素替代疗法 更年期的治疗(ERT)和肥胖是主要的危险因素。这个 后者的作用可能是由于绝经后妇女 肥胖和循环中生物可利用的雌激素水平。口服避孕药和 怀孕，两者都对子宫内膜产生雌激素刺激，但 在孕激素的持续调节作用下，与 降低风险。联合激素替代疗法，其中孕激素 在月经周期的全部或部分时间内加入雌激素会导致没有 与不使用激素的人相比，子宫内膜癌风险增加 替补。尽管ERT和肥胖是主要的风险因素， 只有一小部分使用ERT的女性，甚至是极度肥胖的女性会 患上子宫内膜癌。从公共卫生的角度来看，这也是重要的 从机械论的观点来看，能够预测哪些女性会成为女性。我们 建议评估一系列8个候选基因(CYP17，CYP19，HSD17B1， 在雌激素生物合成、反式激活中的作用 以及新陈代谢途径，以确定这些危险因素的影响是否 通过遗传变异来调节或改变。我们将对这个问题进行评估 在对13.3万名女性进行的前瞻性流行病学研究的背景下 加州教师(加州教师研究)采用嵌套病例对照研究 设计。我们还将详细研究植物雌激素对 子宫内膜癌风险降低与激素替代疗法、肥胖和 八个候选基因正在评估中。

DESCRIPTION (provided by applicant): The etiology of endometrial cancer is relatively well understood. Estrogen stimulation of the endometrium without the modulatory effects of progestins is the major cause. Estrogen replacement therapy (ERT) in menopause and obesity are the principal risk factors. The effect of the latter is probably due to the association between postmenopausal obesity and circulating bioavailable estrogen levels. Oral contraceptives and pregnancy, both of which deliver estrogen stimulation to the endometrium but with the continuous modulatory influence of progestins, are associated with reduction in risk. Combination hormone replacement therapy in which a progestin is added to estrogen for all or part of the monthly cycle results in no increase in endometrial cancer risk over that of a non-user of hormone replacement. Despite the fact that ERT and obesity are the major risk factors, only a small proportion of women using ERT or even with extreme obesity will develop endometrial cancer. It would be important from a public health as well as from a mechanistic view to be able to predict which women those will be. We propose to evaluate a series of eight candidate genes (CYP17, CYP19, HSD17B1, ER, CYP1A1, CYP1B1, COMT andPR) in the estrogen biosynthesis, transactivation and metabolism pathways to determine if the effects of these risk factors might be mediated or modified by genetic variability. We will evaluate this question in the context of a prospective epidemiologic study of 133,000 female California teachers (the California Teachers Study) using a nested case-control design. We will also examine in detail the possible impact of phytoestrogens on endometrial cancer risk reduction in conjunction with HRT, obesity and the eight candidate genes under evaluation.