Targeted Approaches to Overcoming Endocrine Resistance in Breast Cancer.

摘要

The research outlined in this proposal is aimed directly at improving the effectiveness and duration of endocrine therapies. Our approach builds upon our initial observations that tamoxifen up-regulates 14-3-3 , a key scaffold protein that is associated with poor outcome of patients on tamoxifen endocrine therapy. 14-3-3 interacts with and enhances the activity of growth factor receptors and kinases that are overexpressed in breast cancers that are resistant to endocrine therapies. The experiments outlined are aimed at validating 14-3-3z as a marker for risk of recurrence due to the development of endocrine resistance and at establishing this protein as a target whose inhibition would enhance the effectiveness of endocrine therapies, by maintaining endocrine sensitivity. Thus, the outcome of this research has the potential for improving the selection of breast cancer patients most likely to benefit from endocrine therapies and provide a new avenue for enhancing the effectiveness of these therapies for treatment of breast cancer.