CLINICAL SIGNIFICANCE OF FUNCTIONALLY DEFECTIVE ESTROGEN RECEPTOR

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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.