IDENTIFYING TARGETS OF E3 UBIQUITIN LIGASES:ROLE IN BRCA1-MEDIATED BREAST CANCER

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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. Breast cancer is the second leading cause of cancers deaths in women in the United States. It is estimated that between 5-10% of breast cancers have a heritiable basis, and mutations in breast cancer susceptibility gene 1 (BRCA1) gene contribute significantly to the development of these cancers. BRCA1 is a tumor suppressor protein that inhibits the uncontrolled proliferation of cells, in part, by promoting the destruction of other cellular proteins as an E3 ubiquitin (Ub) ligase. Current methods for identifying targets of E3 Ub ligases have met with limited success. As a result, it is largely unclear which cellular proteins BRCA1 breaks down or degrades. The long-term goal of our research is to understand how protein degradation leads to cellular proliferation and tumor development. The objective of this proposal is to develop an innovative strategy to isolate targets of E3 Ub ligases (which includes BRCA1), relating the expression of BRCA1 targets to its anti-proliferative activity. To test this hypothesis, we will use a variety of virological, biochemical, and cell biology techniques to develop this system and identify BRCA1 targets. The primary rationale for these studies is to characterize the molecular events in the initiation of breast cancer. Results from our studies will be significant because the cellular proteins we will identify with our strategy can be used as potential diagnostic markers in the detection of and as therapeutic targets in breast tumorigenesis.