CLINICAL SIGNIFICANCE OF FUNCTIONALLY DEFECTIVE ESTROGEN RECEPTOR

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。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，但不一定是研究者所在的机构。 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。 使用烷基化和同位素编码质谱，我们开发了方法来定量ER的氧化损伤程度，以期将来自乳腺肿瘤样本的分析数据与对各种治疗的反应的临床数据相关联。 我们现在正在编目ER的其他翻译后修饰，如磷酸化，这可能会影响其生物活性和它在乳腺癌发展中可能发挥的任何作用。 我们最近报道了一个新的磷酸化位点中的关键N-末端结构域的ER。 我们正在探索这一点的生物学意义，以及我们观察到但尚未报道的其他以前未知的修饰。 这些研究的长期目标是开发基于抗体的测试，以预测特定患者对特定治疗方法的可能反应。

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. Using alkylation and isotope coded mass spectrometry, we developed 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. We are now 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. We have recently reported the finding of a new phosphorylation site in the critical N-terminal domain of ER. We are probing the biological significance of this and other previously unknown modifications that we have observed but not yet reported. The long-term objective of these studies is to develop antibody-based tests that will predict the likely response of particular patients to specific therapeutic approaches.