NORMAL BREAST ESTROGEN RESPONSE & BREAST CANCER ETIOLOGY

我们的总体目标是确定乳腺上皮中允许零星乳腺癌发展的分子/生理环境，特别是与雌激素暴露有关的乳腺癌，并将这一知识转化为预防策略。到目前为止，我们的工作已经证明，与未患乳腺癌的女性(对照组)相比，患有乳腺癌的女性(病例)的乳房过度表达雌激素受体α。此外，我们有证据表明，在高危乳房中，雌激素对ERα的自体下调失败。这些数据是使用新鲜冷冻的正常乳腺组织从接受乳房手术的妇女身上开发出来的，因此不易重现。我们现在建议进行一项验证性研究，使用一个新的病例对照数据集，该数据集包括400名从病理科档案中检索到的石蜡包埋的乳房组织。该数据集已经汇编完毕，包括详细的乳腺癌风险数据以及有关月经周期日期和外源性激素使用的信息。我们将利用这组女性来检验以下假设：1)ERα在正常乳腺上皮中表达更频繁，水平更高：2)增殖率(即Ki-67标记)较高，3)与良性疾病对照组相比，乳腺癌患者乳腺上皮中的凋亡率(即TUNEL阳性细胞)较低。这些分析将检验被广泛接受的概念，即雌激素通过促进增殖而促进乳腺癌的病因，并将提供关于细胞无序死亡的重要性的关键新信息。最后，由于缺乏月经周期数据，研究绝经前妇女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月经周期阶段而波动。我们将测试一种使用乳腺上皮样本的组织学评估来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，将为未来对易患癌症的乳腺进行乳腺上皮生物学的检查提供一个框架，并指出可以被扰乱或促进乳腺癌预防的途径。回顾评估月经周期阶段的能力将导致在绝经前妇女中利用大量石蜡包埋组织进行类似研究的能力。

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.