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

西方的生活方式，包括饮食类型，缺乏体力活动和某些生育模式，与乳腺癌，子宫内膜癌和卵巢癌的高风险有关。一个普遍的观点是，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介导的。所有三种癌症的一个潜在的共同特征是卵巢雄激素的过度生产。第二个共同特征可能是胰岛素或胰岛素样生长因子-I（IGF-I）的血浆和组织水平升高，或IGF结合蛋白降低。胰岛素是调节能量代谢的关键激素，并且与胰岛素样生长因子-I一起，也是调节合成代谢（生长）过程的中心，作为可用能量和基本底物（例如，氨基酸）。IGF-I水平升高或IGF-binding proteins（IGFBPs）水平降低可通过抑制细胞凋亡和刺激细胞增殖促进肿瘤的发生。此外，胰岛素和IGF-I可增强卵巢雄激素的产生，并下调肝脏SHBG的产生和血浆水平。本提案的具体目的是解决以下假设：胰岛素的血浆水平升高（诊断前）;和/或主要IGFBP（IGFBP-1、IGFBP-2、IGFBP-3）的给定浓度的血浆IGF-I升高与年轻女性中卵巢癌和子宫内膜癌以及乳腺癌的风险升高相关。通过胰岛素和IGF-I，该研究试图建立暴露于西方生活方式与营养过剩和类固醇激素失衡之间的联系，这些激素被认为与最常影响女性的三种癌症有关。本研究是一组三项并行研究的组成部分（组成部分3），这些研究涉及内源性激素在卵巢癌和子宫内膜癌以及年轻女性乳腺癌病因学中的作用的互补方面。所有研究均基于相同的基础人群，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).