This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Women begin to face their greatest fear when they have been told that their routine mammogram or breast exam is abnormal. Women experience an array of symptoms throughout the course of their diagnosis, treatment and recovery from breast cancer. Symptoms are perceived indicators of change in normal functioning as experienced by patients. Symptoms disrupt daily functioning, most notably social function and communication. Symptom outcomes impact functional and emotional status, health care service utilization, mortality/morbidity, financial status, and self-care/management. Research has demonstrated the presence of significant associations between symptoms experienced by breast cancer survivors, suggesting a complex web of symptom experience. The nature of the complex interactions between symptoms remains unclear. Patients with one symptom are likely to have others, as well. Cancer-related fatigue, depressive-anxiety symptoms and sleep disturbances are the most frequent symptoms experienced by women diagnosed with breast cancer. These symptoms can have a devastating impact on their quality of life. Recent studies imply a correlation of these symptoms with selected markers of inflammation including levels of proinflammatory cytokines. Systemic Biomarkers: Biomarkers like carcinoembryonic antigen, CA-125 and prostate-specific antigen (PSA) are helpful in monitoring and in some cases diagnosing cancer (41). Three new serum biomarkers derived from membrane proteins found on breast cancer cells, Aminopeptidase N (CD13), membrane type 1-matrix metalloproteinase (MT1-MMP), and stromal derived receptor-1 (SDR-1), are hopeful novel biomarkers that may prove useful in the diagnosis of breast cancer. Aminopeptidase N, also known as CD13, is a membrane-bound, zinc-dependent peptidase that cleaves neutral amino acids from the N terminus of oligopeptides. In addition to being expressed by a number of tissues, CD13 is aberrantly upregulated on both the tumor cells and developing blood vessels of cancerous tissue. Accumulating evidence points to CD13 as a key regulator in this tissue of both angiogenesis, or new blood vessel formation (42, 43), and the migration and invasion of tumor cells (44, 45). Interestingly, although CD13 was first defined as a membrane bound protein, a soluble form was later detected in a variety of bodily fluids including blood. Moreover, a number of studies have shown CD13 to be elevated in the serum of cancer patients, and to correlate with larger tumor size (46, 47). To date, however, no studies have investigated CD13 serum activity as a prognostic marker. Membrane type 1-matrix metalloproteinase (MT1-MMP) also shares similar characteristics as CD13. It is expressed as an inactive cell surface proteinase which is induced under breast cancer progression and angiogenic responses (48-50). Interestingly, the functional activation of MT1-MMP results in increased cell migration and invasion and has been shown to be actively translocated to the cell surface in hypoxia, both in vitro and in human breast cancer (51). It has also been shown to be shed from tumors as an active fragment which can be detected by MT1-MMP-specific fluorescent peptide substrates (52, 53). The third biomarker is a novel cell surface protein which is over-expressed in human breast cancer and is selective for a highly invasive ductal carcinoma; high expression predicts distant metastasis (54). This cell surface protein also depicts cleaved protein isoforms in human breast tumor lysates indicating it may be shed in blood. This novel tumor antigen was identified from a breast cancer patients sentinel lymph node and an antibody directed against it was synthesized. This unique antibody will be used in a fluorescent-based assay on blood samples to determine whether it is a potential diagnostic marker.
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