CLINICAL SIGNIFICANCE OF FUNCTIONALLY DEFECTIVE ESTROGEN RECEPTOR

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定是研究者机构。在40%的雌激素受体（ER）阳性乳腺肿瘤中观察到ER的DNA结合功能丧失，这被认为是当抗雌激素他莫昔芬作为复发性疾病的一线治疗时许多ER阳性乳腺癌患者未能应答的主要原因。我们的项目的目的是确定和表征解释所观察到的ER-DNA结合功能缺陷的翻译后分子机制，从而能够设计未来的治疗方式来逆转或预防这种ER缺陷，从而恢复内分泌敏感性。特别是，我们正在开发的方法，以确定方法来定量的氧化损伤的程度，ER的烷基化和同位素编码的质谱法，以期相关的分析数据，从乳腺肿瘤样本和临床数据对各种治疗的反应。长期目标是开发能够预测特定治疗方法结果的测试。我们也正在对ER的其他翻译后修饰进行编目，例如磷酸化，这可能会影响其生物活性及其在乳腺癌发展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 we are developing methods to determine methods to quantitate the degree of oxidative damage to ER by alkylation and isotope coded mass spectrometry, 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 also are 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.