SOY AND ESTROGEN INTERACTIONS IN THE BREAST

描述(申请人提供)：在女性的人口统计学和观察性研究中，饮食大豆的摄入与乳腺癌风险的降低有关，而且在生命早期食用大豆的保护作用似乎更强。啮齿动物研究已经证明，对早期接触大豆异黄酮的动物具有深远的保护作用。我们在绝经后猴子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。我们已经证明了猴子模型对绝经后环境中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房发育的研究，而青春期乳房发育很难在人类患者中进行研究。我们假设，在青春期食用大豆会减少乳房的增殖，诱导乳房分化，并减少荷尔蒙对发育中的乳房的暴露；这种影响可以解释为什么在生命早期接触大豆的妇女和动物患乳腺癌的风险较低。为了验证这一假设，我们建议随机选择40只青春期前雌性食蟹猴，让它们接受高大豆饮食(模拟添加大豆的饮食)或不食用大豆(模拟典型的北美饮食)，并通过乳房活检和血清收集重复采样，纵向跟踪它们在月经初潮和青春期乳房发育的整个过程。我们的具体目标是：1)确定乳房组织对青春期食用大豆的反应；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)确定乳房内雌激素和调节乳房局部雌激素产生的酶；以及4)探索可能受大豆消费调控的乳腺上皮基因表达模式。这项拟议的工作将提供一个独特的视角，在一个与人类具有高度遗传和生理相似性的灵长类动物模型中，原本无法进入的乳房发育期。

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.