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，特别是与雌激素暴露有关的环境，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，乳腺癌妇女的乳房（病例）过度表达雌激素受体α，相对于没有乳腺癌妇女的乳房（对照组）。此外，我们有证据表明，在高风险乳房中，雌二醇对ER α的自体下调失败。这些数据是从接受乳房手术的妇女的新鲜冷冻正常乳房组织中获得的，因此不容易重复。我们现在提出一项验证性研究，使用从病理科档案中检索的400名妇女石蜡包埋乳房组织的新病例对照数据集。这个数据集已经收集好了，包括详细的乳腺癌风险数据以及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验证以下假设：1)ER α在正常乳腺上皮中的表达频率更高，表达水平更高；2)与良性疾病对照相比，乳腺癌病例的乳腺上皮的增殖率（即Ki-67标记）更高；3)凋亡率（即TUNEL阳性细胞）较低。这些分析将检验人们普遍持有的观念，即雌激素通过增加增殖促进乳腺癌病因学，并将提供有关细胞无序死亡重要性的重要新信息。最后，由于缺乏月经周期数据，检查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分类月经周期阶段的方法，如果这些研究结合在一起，将为未来易患乳腺的乳腺上皮生物学检查提供一个框架，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使我们能够利用大量石蜡包埋组织在绝经前妇女中进行类似的研究。

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.