BIOLOGICAL MARKERS OF BREAST CANCER & TAMOXIFEN RESPONSE

该计划项目的总体目标是增加我们对雌激素在乳腺癌发展中的作用的了解。我们将使用遗传学和生化方法解决非裔美国人和高加索女性乳腺癌风险决定因素的使用问题。我们将使用遗传学和生化方法来解决非裔美国人和高加索女性中乳腺癌风险决定因素的问题。我们还将在两个相互关联的临床试验中，通过评估风险增加的女性对选择性雌激素受体修饰剂(SERM)三苯氧胺的反应，来评估改变乳腺上皮细胞对雌激素暴露的临床实用性。因此，该项目的总体目标是：1)通过分析一组与非裔美国人和高加索女性乳腺癌患者的激素代谢和对DNA损伤的反应有关的乳腺癌易感等位基因和一组匹配的对照组，建立乳腺癌风险的遗传模型；2)通过分析非裔美国人和高加索女性乳腺癌患者和匹配的对照组女性雌激素代谢的个体间变异性，建立乳腺癌风险的生化模型，所有这些人都已进行了与激素代谢相关的易感等位基因的基因分型；3)通过将建议的乳腺癌易感等位基因的基因数据与通过研究病例与对照中的雌激素代谢而开发的生化风险曲线相结合，开发乳腺癌风险的药物遗传学模型；4)评估MRI定义的乳腺体积变化作为终点的反应；5)使用外周血中氧化损伤的标记物和MRI所见密度增加区域的免疫组织化学评估，确定对他莫昔芬的反应的生物标志物。在这项研究的结论中，我们将基于一系列雌激素效应的测量方法开发出一个全面的乳腺癌风险模型，该模型适用于非裔美国人和高加索人，我们将测试他莫昔芬改变替代风险测量方法的能力。此外，我们还将评估三苯氧胺改变风险替代措施的能力。此外，我们将评估MRI检测到的乳房改变作为替代终点的可能性，并积累关于一系列组织病理损害的数据，这些数据也可以用作替代终点。

The overall goal of this Program Project is to increase our understanding of the contribution of estrogen to the development of breast cancer. We will address the use of breast cancer risk determinants in both African American and Caucasian women using a genetic, as well as a biochemical approach. We will address the issue of breast cancer risk determinants in both African American and Caucasian women using a genetic, as well as a biochemical approach. We also will evaluate the clinical utility of modifying breast epithelial exposure to estrogen by assessing the response of women at increased risk to the Selective Estrogen Receptor Modifier (SERM) Tamoxifen in two inter-related clinical trials. Thus the overall goals of the project are: 1) To develop a genetic model of breast cancer risk by analyzing a panel of proposed breast cancer susceptibility alleles related to hormone metabolism and response to DNA damage in African American and Caucasian women with breast cancer and a matched set of controls; 2) To develop a biochemical model of breast cancer risk by analyzing interindividual variability in estrogen metabolism in African American and Caucasian women with breast cancer and a matched set of controls, all of whom have been genotyped for the susceptibility alleles related to hormone metabolism; 3) To develop a pharmacogenetic model of breast cancer risk by combining genotypic data on the proposed breast cancer susceptibility alleles with the biochemical risk profile developed by studying estrogen metabolism in cases vs. controls; 4) To evaluate the response of MRI-defined alteration in breast volume as endpoints; 5) To identify biologic markers of response to Tamoxifen using markers of oxidative damage in peripheral blood and immunohistochemical evaluation of regions of increased density seen with MRI. At the conclusion of this study, we will have developed a comprehensive model for breast cancer risk based on a range of measures of estrogen effect that is applicable to both African Americans and Caucasians and we will have tested the ability of Tamoxifen to alter surrogate measures of risk. In addition, we will have evaluated the ability of Tamoxifen to alter surrogate measures of risk. In addition, we will have evaluated the potential of MRI-detected breast changes as surrogate endpoints and accumulated data on a range of histopathologic lesions that may be used as surrogate endpoints as well.