Puberty & Cancer Initiation: Environment Diet & Obesity

乳腺癌是当今美国女性癌症死亡的第二大原因，每年夺走4万人的生命。一些因素，包括对生育的社会影响、饮食和环境化学物质，被认为是影响这个国家乳腺癌高发病率的因素。生殖因素在美国发病率上升中尤为重要，两个主要因素是月经初潮年龄的抑郁和首次足月妊娠前的延长。月经初潮时抑郁的原因尚不完全清楚，但似乎部分是由于饮食，而推迟生育主要是社会原因。因为乳房的当代发育和成熟是 在从月经初潮到怀孕的这段延长的时间里，有毒影响还有更多的时间来有机会诱导肿瘤形成。我们的假设是，围产期和儿童期的饮食，特别是脂肪酸和植物雌激素的组成和数量，决定了儿童的肥胖水平，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，肥胖症确定青春期的途径主要由肾上腺(肾上腺)或卵巢(卵巢)驱动，后者与月经初潮早期和随后的乳腺癌风险有关。在从子宫内到3岁和6到12岁的前瞻性队列中，我们将测试饮食和肥胖的关系，以及环境因素，如内分泌干扰物和致癌物，以及心理社会环境的质量与青春期途径的关系。通过对激素、生长因子和芳香酶的分析，我们将研究饮食调节这些效应的机制。在啮齿动物研究中，我们将检验这样一种假设，即子宫和早期生命中的饮食脂肪酸和植物雌激素成分会改变青春期和乳腺的成熟。我们进一步预测，这些因素会改变乳腺最容易受到致癌侮辱的生命阶段。利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，这些特征可用于检测内源性和外源性化合物的致癌潜力，并在动物模型和人类研究中更好地定义启动的乳腺细胞。

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.