DEGRADOMIC AND PEPTIDOMIC BIOMARKERS FOR EARLY-STAGE 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. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. None of the available circulating tumor markers is recommended for screening, diagnosis, staging, or surveillance of early-stage breast cancer. The need to develop clinically useful biomarkers is particularly urgent for women whose tumors do not overexpress the estrogen receptor (ER), progesterone receptor (PR) and the human epidermal growth factor receptor 2 (HER-2). These so-called "triple negative" breast cancers are clinically characterized as more aggressive and associated with poorer overall patient prognosis. Cancer progression, invasion, and metastasis require and/or bring about changes to tumor microenvironments that involve protein degradation by cancer degradome proteases. Protein substrate degradation products (i.e., peptidome) therefore afford a potentially rich pool for cancer biomarker discovery. Recently, PNNL investigators developed a high-resolution FT MS/MS-based approach for degradome analyses. Initial application of this strategy in a comparative analysis of pooled plasma samples resulted in the discovery of highly selective substrate proteolysis in blood plasma that distinguish early-stage cancer patients from healthy controls. Our specific aims are to identify endogenous peptidome components in tissue and plasma from patients with triple-negative breast cancer, and to determine whether any of these peptidome components can serve as a sensitive and specific predictive marker of response to therapy and survival. This project is expected to have a major effect on public health by allowing detection of breast cancer at an early stage. In addition, the identification of breast cancer-specific protein degradation products may lead to discovery of novel prognostic factors and targets for therapy.