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，每年夺去4万人的生命。有几个因素，包括对生育，饮食和环境化学品的社会影响，被认为是影响乳腺癌在这个国家的高发病率。在美国，生殖因素在发病率增加中尤为重要，两个主要因素是初潮年龄的降低和首次足月妊娠前时间的延长。初潮年龄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 在从初潮到怀孕的这段延长的时间内，还有更多的时间使毒性影响有机会诱导肿瘤形成。我们的假设是，饮食，特别是脂肪酸和植物雌激素的组成和数量，在围产期和儿童期决定肥胖的水平，并调节幼儿的激素环境。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（肾上腺初显）或卵巢（乳房初显）驱动，后者与早期月经初潮和随后的乳腺癌风险有关。在子宫内至3岁和6至12岁的前瞻性队列中，我们将测试饮食和肥胖以及环境因素（如内分泌干扰物和致癌物）和心理社会环境质量与青春期途径的相关性。通过对激素、生长因子和芳香化酶的分析，我们将研究饮食可能介导这些效应的机制。在啮齿动物研究中，我们将检验子宫内和生命早期的膳食脂肪酸和植物雌激素组成改变青春期和乳腺成熟的假设。我们进一步预测，这些因素会改变乳腺最容易受到致癌物侵害的生命周期。利用基因表达阵列的力量，我们将定义启动乳腺上皮细胞的特征，这些特征可用于检查内源性和外源性化合物的致癌潜力，并在动物模型和人体研究中更好地定义启动乳腺细胞。

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.