Soy Consumption and Breast Tissue Proliferation

描述（由申请人提供）：在基于生物疗法的CAM领域，大豆和异黄酮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警告可能会增加乳腺组织中的细胞增殖和雌激素活性。鉴于健康妇女和乳腺癌幸存者对健康的主张以及大豆食品和异黄酮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，特别是对幸存者的不良影响。这个项目的假设是一生中大豆摄入量高的女性在乳房组织中的增殖比大豆摄入量低的女性要低，因为她们从小就经历了大豆的保护作用。与此同时，我们提出，成年期高大豆摄入量和早期低大豆摄入量的女性比终生高大豆摄入量的女性在乳房组织中有更大的增殖。这项研究将涉及以下具体目标：研究白种人和日本血统妇女在生命中不同时期食用大豆与正常和癌变乳腺组织增殖标志物之间的关系；2. 通过检测正常和癌性乳腺组织中孕酮受体的表达，确定定期摄入大豆是否会对乳腺细胞产生雌激素效应；和3。探讨雌激素受体β在正常和癌乳腺组织对大豆摄入的反应中的作用。这项调查将包括来自一项关于乳腺密度的巢式病例对照研究的日本和高加索妇女，这是一项多种族队列研究的子研究。队列成员完成了一份有效的食物频率问卷。在巢式病例对照研究中，妇女也按生命阶段报告了她们一生的大豆史。组织库是夏威夷肿瘤登记处的一部分，收集了1995年在夏威夷诊断的所有癌症病例中约85%的废弃病理材料，并且正在连续多年收集标本。潜在的研究对象将从1995年至1998年间诊断出的400例乳腺癌病例中招募，并将其作为频率匹配的对照组，这些对照组此前曾做过乳房活检。根据85%的全州覆盖率和70%的预期参与率，我们估计我们可以将240例乳腺癌病例的肿瘤组织纳入其中。此外，我们预计将在大约160例乳腺癌妇女和大约60例既往活检的对照妇女的标本中获得正常乳腺组织。组织阵列将使用微阵列技术从石蜡包埋的组织块制备。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学测量。在染色的组织阵列上，我们将检查两个互补的增殖标志物，Ki67和PCNA，它们在石蜡块上起作用，随着时间的推移几乎没有下降。此外，我们将评估作为乳腺“雌激素效应”标志的孕激素受体表达，以及作为激素反应性指标的雌激素受体α和β。我们将运用多元回归模型，对潜在混杂因素进行校正，以探讨组织病理学特征作为因变量与大豆摄入量的不同测量值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.