The receptor tyrosine kinase encoded by the erbB1 proto-oncogene plays an important role in normal cellular growth and differentiation. Moreover, ErbB1 receptors are frequently overexpressed in various human tumor cell lines and malignancies including cancers of the bladder, brain, breast, lung, ovary, and prostate gland. It is believed that erbB1 overexpression may cause increased receptor signaling and cellular transformation, and, therefore, may play a role in the etiology of these cancers. In addition to full-length ErbB1 receptors, normal and malignant cells and tissues produce """"""""soluble"""""""" ErbB1 (sErbB1) analogs that embody only the extracellular domain of the receptor. Recently, our laboratory has identified two alternative erbB1 transcripts of 1.8 kb and 3.0 kb in normal human tissues that encode 60-kDa and 110-kDa sErbB1 proteins, respectively. We also have identified a 110-kDa sErbB1 protein in human sera, and have developed an acridinium-linked immunosorbent assay (ALISA) to quantify this molecule in human body fluids. ALISA analyses show that serum p110 sErbB1 levels differ significantly between healthy men (median = 24,512 fmol/ml; range = 6,751 to 48,826 fmol/ml) and women (median = 3,716 fmol/ml; range = 467 to 61,583 fmol/ml) (Baron et al., 1998, J. Immunologic Methods, in press) [1], and that women with stage III or IV epithelial ovarian cancer (EOC) (median = 284 fmol/ml; range = 30 to 1,350 fmol/ml) have significantly lower serum p110 sErbB1 levels than healthy women (median = 6,395 fmol/ml; range = 1,846 to 23,708 fmol/ml) of similar ages (Baron et al., submitted)[2]. Taken together, these data have led us to hypothesize that a low serum p110 sErbB1 level may be a diagnostic biomarker for various erbB1 overexpressing cancers. We propose, therefore, to examine p110 sErbB1 levels in patients with advanced or high grade bladder, brain, breast, lung, or prostate cancer by ALISA, and to compare p110 sErbB1 levels between these patients and healthy subjects matched for specific risk factors such as age, gender, race, and smoking history. This pilot study will allow us to determine whether low p110 sErbB1 levels may be a useful biomarker to detect these tumors. The proposed study also will lay the foundation for future studies focused on determining the utility of p110 sErbB1 as a marker of pre-symptomatic, early stage and/or aggressive tumors. The systematic characterization of tumor-associated biomarkers, especially oncogene-derived biomarkers, may one day determine the timing and type of treatment that a cancer patient receives and, thus, ultimately impact on patient morbidity and mortality.
