) Members of the erbB receptor family are commonly amplified and/or overexpressed in various tumor cell lines and human malignancies, where it is believed that increased signaling is important in tumor etiology and progression. ErbB receptor family members are being investigated rigorously as biomarkers of cancer. Several studies demonstrate that cells produce """"""""soluble"""""""" ErbB analogs in addition to their holoreceptors. These sErbB proteins embody only the extracellular domain of the receptor; they are secreted or proteolytically released into the pericellular space and are present in body fluids. Recently, our laboratory has identified two alternate transcripts of the erbB1 proto-oncogene and several putative sErbB1 proteins in human sera. To further the biochemical characterization of sErbB1 proteins, and to understand better their potential role as markers of disease activity, we have generated monoclonal antibodies toward defined peptide epitopes of the ErbB1 extracellular domain. We have also developed an acridinium-linked immunosorbent assay (ALISA) to quantify sErbB1 molecules in patient body fluids. Studies with stage III/IV epithelial ovarian cancer patients indicate that sErbB1 levels are altered in the majority of these patients relative to normal subjects. However, 8 of the 59 ovarian cancer patients studied have sErbB1 levels comparable to those of disease-free subjects. Interestingly, the median survival time of this group of 8 patients is nearly double that of the 51 patients with altered sErbB1 levels, suggesting that sErbB1 levels may be potential prognostic biomarkers. These observations had lead us to hypothesize that sErbB1 molecules inhibit cellular growth normally, and that reduced levels of sErbB1 may unrestrain cell division in malignant tissues. We further hypothesize that sErbB1 analogs may be valuable prognostic tumor biomarkers.
The specific aims of this proposal are, therefore, to: 1) characterize biochemically sErbB1 analogs present in the sera of normal and ovarian cancer patients, 2) standardize, validate, improve, modify, and automate our current sErbB1 ALISA, and 3) expand our analysis of sErbB1 levels in stage III/IV epithelial ovarian cancer patients to a much larger population of ovarian cancer patients, to determine if sErbB1 level is associated with either patient survival or any known prognostic factors of this disease. The goals outlined, here, will further my training in the fields of epidemiology, biostatistics, clinical research and oncology, thus broadening my previous training in developmental biology, cell biology, and immunology. These goals will prepare me for an independent, academic career in the field of cancer prevention and control.
