SOY AND ESTROGEN INTERACTIONS IN THE BREAST

描述（由申请人提供）：在女性人口统计学和观察性研究中，食用大豆与降低乳腺癌风险有关，并且在生命早期食用大豆的保护作用似乎更强。啮齿类动物研究已经证明，早期接触大豆异黄酮对动物有深远的保护作用。我们在绝经后的猴子模型中的数据清楚地显示了大豆对乳房的抗增殖作用，我们还观察到大豆的摄入减少了乳房的雌激素暴露。我们已经证明了猴子模型在绝经后环境下乳腺癌风险的预测价值，我们认为该模型特别适用于研究青春期乳房发育，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房增生，诱导乳房分化，并减少发育中的乳房的激素暴露；这样的效应可以解释为什么早期食用大豆的女性和动物患乳腺癌的风险较低。为了验证这一假设，我们建议随机选取40只青春期前雌性食蟹猴，让它们接受高大豆饮食（模拟大豆补充饮食）或不食用大豆饮食（模拟典型的北美饮食），并通过乳房活检和血清采集反复取样，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)确定青春期乳腺组织对大豆摄入的反应；2)测定日粮中添加大豆对初潮和月经周期卵巢激素的影响；3)测定组织内雌激素和调节乳腺局部雌激素产生的酶；4)探讨大豆摄入对乳腺上皮基因表达的影响。这项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，其他难以接近的乳房发育时期。

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.