Puberty & Cancer Initiation: Environment Diet & Obesity

青春期

• 批准号: 6805149
• 负责人: SUE C HEFFELFINGER
• 金额: $ 136.59万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-29 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6805149
• 关键词: breast neoplasms; clinical research; cooperative study; environment related neoplasm /cancer; human puberty; nutrition related neoplasm /cancer; obesity

Breast cancer is the second leading cause of cancer deaths among women in the U.S. today, claiming 40,000 lives per year. Several factors, including societal influences on childbearing, diet, and environmental chemicals are believed to be impacting the high rate of breast cancer in this country. Reproductive factors are particularly important in the increased incidence in the U.S., two major factors being the depression in the age of menarche and the extension in the time before first full-term pregnancy. Reasons for the depression in the age of menarche are not fully understood, but appear to be due in part to diet, whereas the delay of childbearing is primarily social. Because the contemporary development and maturation of the breast is during this extended time from menarche to pregnancy, there is further time for toxic influences to have an opportunity to induce tumor formation. Our hypothesis is that diet, in particular fatty acid and phytoestrogen composition and quantity, during the perinatal period and childhood determine the level of adiposity and regulate the hormonal milieu in young children. Through leptin and insulin-like growth factor, adiposity determines the pathway of puberty as being driven primarily by the adrenal gland (adrenarche) or ovaries (thelarche), the latter being associated with early menarche and subsequent risk of breast cancer. In prospective cohorts from in utero to age 3 and age 6 to 12, we shall test the association of diet and adiposity, as well as environmental agents, eg endocrine disruptors and carcinogens, and qualities of the psychosocial environment, with pubertal pathway. Through analysis of hormones, growth factors, and aromatase we shall examine mechanisms through which diet may mediate these effects. In rodent studies we shall test the hypothesis that dietary fatty acid and phytoestrogen composition in utero and early life alter puberty and mammary gland maturation. We further predict that these factors alter the periods of life at which mammary glands are most susceptible to carcinogenic insults. Using the power of gene expression arrays we shall define characteristics of initiated mammary epithelial cells that can be used to examine endogenous and exogenous compounds for their carcinogenic potential and better define initiated mammary cells in animal models and human studies.

乳腺癌是当今美国妇女癌症死亡的第二大原因，每年夺走40,000人生命。据信，包括对生育，饮食和环境化学物质的社会影响在内的几个因素会影响该国乳腺癌的高率。生殖因素在美国发病率的增加中尤其重要，这两个主要因素是初潮时代的抑郁症以及在第一次完整妊娠前的时间延伸。初潮时代的抑郁症的原因尚不完全了解，但似乎部分归因于饮食，而生育的延迟主要是社会的。因为当代乳房的发展和成熟是 在这段时间内从初潮到怀孕期间，有更多的有毒影响有机会诱导肿瘤形成。我们的假设是，在围产期和童年时期，饮食，尤其是脂肪酸和植物雌激素的组成和数量，决定了肥胖水平，并调节了幼儿的荷尔蒙环境。通过瘦素和胰岛素样生长因子，肥胖决定了青春期的途径，主要是由肾上腺（肾上腺结构）或卵巢（Thelarche）驱动的，后者与早期初潮和随后的乳腺癌风险有关。在从子宫到3岁到6岁至12岁的前瞻性队列中，我们将测试饮食和肥胖的关联，以及环境药物，例如内分泌破坏者和致癌物，以及心理社会环境的质量，以及与青春期的途径。通过分析激素，生长因子和芳香酶，我们将检查饮食可以介导这些作用的机制。在啮齿动物的研究中，我们应检验以下假设：饮食中的脂肪酸和植物雌激素成分在子宫和早期生命改变了青春期和乳腺的成熟。我们进一步预测，这些因素改变了乳腺最容易受到致癌性损伤的生命周期。使用基因表达阵列的力量，我们将定义启动的乳腺上皮细胞的特征，这些特征可用于检查其致癌潜力的内源性和外源性化合物，并更好地定义动物模型和人类研究中的乳腺细胞。