SOY AND ESTROGEN INTERACTIONS IN THE BREAST

描述（由申请人提供）：在妇女的人口统计学和观察性研究中，饮食大豆消费与乳腺癌风险降低有关，并且在生命早期食用大豆时，保护作用似乎更强。啮齿类动物研究表明，对在生命早期接触大豆异黄酮的动物具有深远的保护作用。我们在绝经后猴模型中的数据清楚地显示了大豆消费对乳房的抗增殖作用，我们还观察到大豆消费减少了乳房的雌激素暴露。我们已经证明了猴模型对绝经后乳腺癌风险的预测价值，我们相信该模型特别适用于青春期乳腺发育的研究，这在人类患者中很难研究。我们假设青春期食用大豆可减少乳腺增生，诱导乳腺分化，并减少发育中乳腺的激素暴露;这种效应可以解释在生命早期暴露于大豆饮食的女性和动物中观察到的乳腺癌风险较低。为了验证这一假设，我们建议将40只青春期前雌性食蟹猴随机分为高大豆饮食（模拟大豆补充饮食）或无大豆饮食（模拟典型的北美饮食），并通过乳房活检和血清采集重复采样，纵向跟踪它们的月经初潮和青春期乳房发育过程。我们的具体目标是：1）确定青春期期间乳腺组织对大豆消费的反应; 2）确定饮食大豆对月经初潮和月经周期期间卵巢激素的影响; 3）确定组织内雌激素和调节乳腺局部雌激素产生的酶;以及4）探索乳腺上皮中可能受大豆消费调节的基因表达模式。拟议的工作将提供一个独特的观点，否则无法进入一个灵长类动物模型的乳房发育时期与人类的遗传和生理高度相似。

DESCRIPTION (provided by applicant): Dietary soy consumption has been associated with decreased breast cancer risk in demographic and observational studies in women, and the protective effects appear to be stronger when soy is consumed earlier in life. Rodent studies have demonstrated profound protective effects for animals exposed early in life to soy isoflavones. Our data in the postmenopausal monkey model clearly show antiproliferative effects of soy consumption on the breast, and we have also observed that soy consumption reduces estrogen exposure of the breast. We have demonstrated the predictive value of the monkey model for breast cancer risk in the postmenopausal setting, and we believe that the model is particularly applicable to studies of pubertal breast development, which is difficult to study in human patients. We hypothesize that dietary soy consumption during puberty reduces breast proliferation, induces breast differentiation, and reduces hormonal exposure to the developing breast; such an effect would explain the observed lower risk of breast cancer in women and animals exposed to soy diets early in life. To test this hypothesis, we propose to randomize 40 pre-pubertal female cynomolgus monkeys to receive either a high-soy diet (modeling a soy-supplemented diet) or no dietary soy (modeling a typical North American diet), and to follow them longitudinally through the course of menarche and pubertal breast development by repeated sampling via breast biopsies and serum collection. Our specific aims are: 1) to determine breast tissue responses to soy consumption during puberty; 2) to determine the effects of dietary soy on ovarian hormones during menarche and menstrual cycling; 3) to determine intratissue estrogens and the enzymes that regulate local estrogen production in the breast; and 4) to explore patterns of gene expression in mammary epithelium which may be modulated by soy consumption. The proposed work will provide a unique view of an otherwise inaccessible period of breast development in a primate model with high genetic and physiologic similarity to human beings.