BIOLOGICAL MARKERS OF BREAST CANCER & TAMOXIFEN RESPONSE

本计划项目的总体目标是增加我们对雌激素对乳腺癌发展的贡献的理解。我们将使用遗传学和生物化学方法来解决非裔美国人和高加索妇女乳腺癌风险决定因素的使用问题。我们将使用遗传学和生物化学方法来解决非裔美国人和高加索妇女乳腺癌风险决定因素的问题。我们还将通过评估两项相互关联的临床试验中对选择性雌激素受体修饰剂（SERM）他莫昔芬风险增加的妇女的反应，评估修饰乳腺上皮暴露于雌激素的临床效用。因此，该项目的总体目标是：1）通过分析一组与激素代谢和对患有乳腺癌的非洲裔美国人和白人妇女的DNA损伤的反应相关的乳腺癌易感性等位基因以及一组匹配的对照，来开发乳腺癌风险的遗传模型;（二）通过分析非裔美国人和白人乳腺癌妇女雌激素代谢的个体间差异，建立乳腺癌风险的生化模型，匹配的对照组，所有这些人都已经进行了与激素代谢相关的易感等位基因的基因分型; 3）通过将拟议的乳腺癌易感等位基因的基因型数据与通过研究病例与对照组的雌激素代谢而开发的生化风险特征相结合，开发乳腺癌风险的药物遗传学模型; 4）评价MRI定义的乳房体积改变作为终点的反应; 5）使用外周血中的氧化损伤标志物和MRI所见的密度增加区域的免疫组织化学评价来鉴定对他莫昔芬的反应的生物标志物。在本研究结束时，我们将根据一系列适用于非裔美国人和高加索人的雌激素效应措施，开发出一个乳腺癌风险的综合模型，我们将测试他莫昔芬改变替代风险措施的能力。此外，我们将评估他莫昔芬改变替代风险指标的能力。此外，我们将评估MRI检测到的乳腺变化作为替代终点的可能性，并积累了一系列组织病理学病变的数据，这些病变也可用作替代终点。

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.