NORMAL BREAST ESTROGEN RESPONSE & BREAST CANCER ETIOLOGY

我们的总体目标是确定乳腺上皮中允许散发性乳腺癌发展的分子/生理环境，特别是当它与雌激素暴露相关时，并将这些知识转化为预防策略。到目前为止，我们的工作已经证明，相对于未患乳腺癌的女性（对照组），患乳腺癌的女性（病例组）的乳房过度表达雌激素受体α。此外，我们有证据表明，在高危乳腺中，雌二醇对ER α的自体下调失败。这些数据是使用来自接受乳房手术的女性的新鲜冷冻正常乳房组织开发的，因此不容易重现。我们现在提出了一个验证性研究，使用一个新的病例对照数据集的400名妇女的石蜡包埋的乳腺组织从病理档案部门检索。这一数据集已经汇编完毕，包括详细的乳腺癌风险数据以及关于月经周期日期和外源性激素使用的信息。我们将使用这组女性来检验以下假设：1）ER α在病例的正常乳腺上皮中表达更频繁且水平更高：2）与良性疾病对照相比，乳腺癌病例的乳腺上皮中增殖率（即Ki-67标记）更高，3）凋亡率（即TUNEL阳性细胞）更低。这些分析将测试广泛持有的概念，雌激素有助于乳腺癌病因通过增加增殖，并将提供关键的新信息的重要性，无序细胞死亡。最后，由于缺乏月经周期数据，检查绝经前女性乳腺上皮特征的流行病学研究受到严重阻碍，因为细胞事件和蛋白质表达随着月经周期阶段而波动。我们将使用乳腺上皮样本的组织学评估来测试对月经周期阶段进行分类的方法，如果这些研究结合在一起，这些研究将为将来检查易患乳腺癌的乳腺上皮生物学提供一个框架，并指出可以中断或促进乳腺癌预防的途径。回顾性评估月经周期阶段的能力将导致能够利用大型石蜡包埋组织库进行绝经前女性的类似研究。

Our overall goal is to define the molecular/physiologic environment in the breast epithelium which permits the development of sporadic breast cancer, particularly as it relates to estrogen exposure, and to translate this knowledge into preventive strategies. Our work so far has demonstrated that the breasts of women with breast cancer (cases) over- express estrogen receptor alpha, relative to the breasts of women without breast cancer (controls). Further, we have evidence suggestive of a failure of autologous down-regulation of ER alpha by estradiol in high risk breasts. These data were developed using fresh-frozen normal breast tissue from women undergoing breast surgery,a nd are not easily reproducible for this reason. We now propose a confirmatory study using a fresh case-control data set of 400 women with paraffin embedded breast tissue retrieved from Department of Pathology archives. This data set has already been assembled, and includes detailed breast cancer risk data and information on menstrual cycle dates and exogenous hormone use. We will use this group of women to test the hypotheses that 1) ER alpha is expressed more frequently and at higher levels in normal breast epithelium of cases: 2) proliferative rates (i.e. Ki-67 labelling) are higher and 3) apoptotic rates (i.e. TUNEL positive cells) are lower in the breast epithelium of breast cancer cases, when compared to benign disease controls. These analyses will test the widely held concept that estrogen contributes to breast cancer etiology via increased proliferation and will provide crucial new information regarding the importance of disordered cell death. Finally, epidemiological studies examining breast epithelial characteristics of premenopausal women are badly hampered by the lack of menstrual cycle data, since cellular events and protein expression fluctuate with menstrual cycle phase. We will test a method of categorizing menstrual cycle phase using histologic assessment of breast epithelial samples which, if together, these studies will provide a framework for future examinations of breast epithelial biology in the cancer-prone breast, and point to pathways that can be disrupted or promoted for breast cancer prevention. The ability to retrospectively assess menstrual cycle phase will lead to the ability to utilize large banks of paraffin embedded tissue for similar studies in pre-menopausal women.