Soy Consumption and Breast Tissue Proliferation

描述(由申请人提供)：在基于生物的疗法的CAM领域中，大豆和异黄酮类药物发挥着越来越大的作用。潜在的好处包括预防癌症、心脏病和更年期症状。然而，一些大豆补充剂的干预措施警告说，乳房组织中的细胞增殖和雌激素活性可能会增加。鉴于健康声明以及健康女性和乳腺癌幸存者中大豆食品和异黄酮类补充剂的摄入量不断增加，迫切需要调查大豆的潜在不良影响，特别是在幸存者中。该项目的假设是，一生中大豆摄入量高的女性乳房组织的增殖程度低于大豆摄入量低的女性，因为她们从小就经历了大豆的保护作用。同时，我们提出，成年后大豆摄入量高的女性和生命早期大豆摄入量低的女性在乳房组织中的增殖程度比一生中大豆摄入量高的女性更大。这项研究将针对以下具体目标：1.研究高加索和日本血统的女性在一生中不同时期食用大豆与正常和癌乳腺组织中增殖标记物的关系；2.根据正常和癌乳腺组织中孕激素受体的表达，确定定期摄入大豆是否对乳腺细胞产生雌激素效应；3.探索雌激素受体Beta在正常和癌乳腺组织对大豆摄入的反应中所起的作用。这项调查将包括日本和高加索女性，这些女性来自一项关于乳房密度的嵌套病例对照研究，这是一项多种族队列的子研究。队列成员完成了一份有效的食物频率问卷。嵌套病例对照研究中的女性还按生命阶段报告了她们一生中的大豆史。组织储存库是夏威夷肿瘤登记处的一部分，收集了1995年期间夏威夷确诊的所有癌症病例中约85%的废弃病理材料，并正在连续几年收集标本。潜在的受试者将从1995至1998年间确诊的400例乳腺癌患者和与其频率匹配的对照组中招募，这些患者之前曾报告过乳房活检。基于85%的全州覆盖率和70%的预期参与率，我们估计我们可以将肿瘤组织包括在240例乳腺癌病例中。此外，我们预计在大约160例乳腺癌患者和大约60名有活检记录的对照女性的样本中可以获得正常的乳腺组织。组织阵列将利用微阵列技术从石蜡包埋的组织块中制备。在组织病理学评估后，我们将对正常乳腺组织进行组织形态计量学测量。在染色的组织阵列上，我们将检测两个互补的增殖标记，它们作用于石蜡切片，随着时间的推移几乎不会下降，Ki67和增殖细胞核抗原。此外，我们将评估孕激素受体的表达作为乳房“雌激素效应”的标志，以及雌激素受体Alpha和Beta的表达作为激素反应的指标。调整潜在混杂因素的多元回归模型将被用来探索组织病理学特征作为因变量，不同大豆摄入量指标作为解释变量之间的关系。

DESCRIPTION (provided by applicant): Within the CAM domain of biologically based therapies, soy and isoflavones play an increasing role. Potential benefits include prevention of cancer, heart disease, and menopausal symptoms. However, a few interventions with soy supplements warned about possible increases in cell proliferation and estrogenic activity in breast tissue. Given the health claims and the growing intake of soy foods and isoflavone supplements among healthy women and breast cancer survivors, it is urgent to investigate the potential adverse effects of soy, especially among survivors. The hypothesis for this project is that women with high soy intake throughout life show lower proliferation in breast tissue than women with low soy intake because they experienced a protective effect from soy since childhood. At the same time, we propose that women with high soy intake in adulthood and low soy intake early in life have greater proliferation in breast tissue than women with high soy intake throughout their life. The study will address the following specific aims: 1. Examine the relation between soy consumption at different times in life and markers of proliferation in normal and cancerous breast tissue among women with Caucasian and Japanese ancestry; 2. Determine whether regular soy intake exerts estrogenic effects on breast cells as assessed by progesterone receptor expression in normal and cancerous breast tissue; and 3. Explore the role of estrogen receptor Beta in the response of normal and cancerous breast tissue to soy intake. This investigation will include Japanese and Caucasian women from a nested case-control study on breast density, a substudy of a multi-ethnic cohort. Cohort members completed a validated food frequency questionnaire. The women in the nested case-control study also reported their lifetime soy history by stage of life. The tissue repository, part of the Hawaii Tumor Registry, has collected discarded pathologic materials, for approximately 85% of all cancer cases diagnosed in Hawaii during 1995 and is in the process of collecting specimens for consecutive years. Potential subjects will be recruited from 400 breast cancer cases diagnosed between 1995 and 1998 and their frequency-matched controls who reported a previous breast biopsy. Based on the 85% statewide coverage and an expected participation rate of 70%, we estimate that we can include neoplastic tissue for 240 breast cancer cases. Furthermore, we anticipate that normal breast tissue will be available in approximately 160 specimens from the women with breast cancer and from approximately 60 control women with previous biopsies. Tissue arrays will be prepared from paraffin-embedded tissue blocks using microarray technology. After histopathologic evaluation, we will perform histomorphometric measurements of the normal breast tissue. On the stained tissue arrays, we will examine two complementary markers of proliferation that work on paraffin blocks and decline little over time, Ki67 and PCNA. In addition, we will assess progesterone receptor expression as a marker of "estrogenic effect" on the breast and estrogen receptors Alpha and Beta as indicators of hormonal responsiveness. Multiple regression models with adjustment for potential confounders will be applied to explore the relation between histopathologic characteristics as the dependent variable with the different measures of soy intake as explanatory variables.