INSULIN, IGF-1 & CANCERS OF BREAST, ENDOMETRIUM & OVARY

西方的生活方式，包括饮食类型、缺乏体育锻炼和某些生育模式，与乳腺癌、子宫内膜癌和卵巢癌的高风险有关。人们普遍认为，生活方式因素对癌症风险的影响是通过激素代谢的改变来调节的。这三种癌症可能共有的一个特征是卵巢雄激素分泌过多。第二个共同特征可能是血浆和组织中胰岛素或胰岛素样生长因子- 1 （igf - 1）水平升高，或igf结合蛋白降低。胰岛素是调节能量代谢的关键激素，与胰岛素样生长因子- 1一起，作为可用能量和基本底物（如氨基酸）的功能，在调节合成代谢（生长）过程中也起着核心作用。igf - 1水平的增加或igf结合蛋白（igfbp）水平的降低已被证明通过抑制细胞凋亡和刺激细胞增殖来促进肿瘤的发展。此外，胰岛素和igf - 1增加卵巢雄激素的产生，下调肝脏分泌和血浆SHBG水平。本建议的具体目的是解决增加（诊断前）血浆胰岛素水平的假设；主要igfbp （IGFBP-1、-2、-3）浓度给定时血浆igf -1升高与年轻女性卵巢癌、子宫内膜癌和乳腺癌风险增加有关。通过胰岛素和igf - 1，该研究试图建立西方生活方式与营养过剩和类固醇激素失衡之间的联系，这些被认为与三种最常影响女性的癌症有关。本研究是一组三个同时进行的研究的组成部分（组成部分3），这些研究解决了内源性激素在年轻女性卵巢癌和子宫内膜癌以及乳腺癌病因学中的互补作用。所有研究均基于相同的潜在人群，通过结合目前正在纽约、于默奥（瑞典）和米兰（意大利）进行的三项前瞻性队列研究获得。

A Western lifestyle, including type of diet, lack of physical activity, and certain childbearing patterns, is associated with high risks of cancers of the breast, endometrium, and ovary. A widely held view is that effects of lifestyle factors on cancer risk are mediated through alterations in hormone metabolism. One feature potentially shared by all three forms of cancer is ovarian overproduction of androgens. A second common feature may be elevated plasma and tissue levels of insulin or insulin-like growth factor-I (IGF-I), or decreased IGF-binding proteins. Insulin is a key hormone in the regulation of energy metabolism and, together with insulin-like growth factor-I, is also central in the regulation of anabolic (growth) processes as function of available energy and elementary substrates (e.g., amino acids). Increased levels of IGF-I, or decreased levels of IGF-binding proteins (IGFBPs), have been shown to promote tumor development by inhibiting apoptosis, and by stimulating cell proliferatton. In addition, insulin and IGF-I enhance ovarian androgen production and down regulate hepatic production and plasma levels of SHBG. The specific aim of the present proposal is to address the hypothesis that increased (prediagnostic) plasma levels of insulin; and/or increased plasma IGF-I for given concentrations of major IGFBPs (IGFBP-1, -2, -3) are associated with increased risk of ovarian and endometrial cancers and of breast cancer in young women. Through insulin and IGF-I, the study seeks to establish a linkage between exposure to Western lifestyle and over nutrition and imbalances in steroid hormones that are thought to be associated with the three cancers most frequently affecting women. This study is a component (Component 3) of a group of three concurrent studies which address complementary aspects of the role of endogenous hormones in the etiology of ovarian and endometrial cancers, and of breast cancer in young women. All studies are based on the same underlying population, obtained by combining three prospective cohort studies that are currently ongoing in New York, Umea (Sweden) and Milan (Italy).