CLINICAL SIGNIFICANCE OF FUNCTIONALLY DEFECTIVE ESTROGEN RECEPTOR

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 雌激素受体(ER)DNA结合功能的丧失在40%的ER阳性乳腺肿瘤中被观察到，这被认为是许多ER阳性乳腺癌患者在接受抗雌激素他莫昔芬作为治疗复发疾病的一线治疗时没有反应的主要原因。我们项目的目标是识别和表征翻译后分子机制(S)，解释观察到的ER-DNA结合功能缺陷，使未来的治疗方案能够逆转或预防这种ER缺陷，从而恢复内分泌敏感性。特别是，利用烷基化和同位素编码质谱学，我们正在开发量化ER氧化损伤程度的方法，以期将来自乳腺肿瘤样本的分析数据与各种治疗反应的临床数据相关联。长期目标是开发能够预测特定治疗方法结果的测试。我们还在对ER的其他翻译后修饰进行分类，例如磷酸化，这些修饰可能会影响ER的生物学活性，以及它在乳腺癌发生中可能发挥的任何作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Loss of the DNA-binding function of estrogen receptor (ER) has been observed in 40% of ER-positive breast tumors and is postulated to be a major reason why many ER-positive breast cancer patients fail to respond when the antiestrogen tamoxifen is given as first-line therapy for recurrent disease. The objective of our project is to identify and characterize the post-translational molecular mechanism(s) accounting for the observed defect in ER-DNA binding function, enabling the design of future therapeutic modalities to reverse or prevent this ER defect and thereby restore endocrine sensitivity. In particular using alkylation and isotope coded mass spectrometry, we are developing methods to quantitate the degree of oxidative damage to ER, with a view to correlating analytical data from breast tumor samples and clinical data on the response to various treatments. The long-term objective is to develop tests that would predict the outcome from particular therapeutic approaches. We are also cataloguing other posttranslational modifications to ER, such as phosphorylation, that may affect its biological activity and any role it may play in breast cancer development.