The p110 isoform of human EGF receptor is differentially expressed in serous vs. mucinous ovarian cancer

Abstract

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Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancies in the US. The epidermal growth factor receptor (EGFR) family of tyrosine kinases plays an important role in the etiology and progression of this disease. Several soluble isoforms of the human EGFR have been described which arise from alternate transcripts. These soluble isoforms (sEGFR) contain sequences that encode only the extracellular domain of the receptor in addition to unique carboxy-terminal sequences¹. One isoform, p110 sEGFR, has potential utility as a serum biomarker for ovarian cancer. We have demonstrated that p110 sEGFR is the major circulating form of EGFR in serum, where it is detected at significantly lower levels in women with EOC². While the EGFR and its related family members have been implicated in ovarian carcinogenesis, previous studies on the expression of EGFR in human EOC have resulted in discordant observations. We predict that some of this discordance is based on the inability of investigators to distinguish between full-length EGFR and its isoforms using IHC. To date, expression of p110 sEGFR in ovarian tissues/tumors has not been studied. We have generated an antibody specific for the unique carboxy-terminal sequence of human p110 sEGFR³. Using this antibody, immunohistochemistry (IHC) was performed on normal ovarian tissue, benign tumors, tumors of low malignant potential (LMP’s), and in all major histologic subtypes of EOC. IHC staining was scored using 3 parameters: intensity(0-3+), percent distribution, and heterogeneity(0-3). We found p110 sEGFR is consistently expressed in the ovarian surface epithelium and in epithelial inclusion cysts in normal ovary. In addition, p110 sEGFR expression in serous tumors (benign cystadenomas, LMP’s, and carcinomas) is higher and more uniform in distribution than in tumors of mucinous differentiation. The expression of p110 sEGFR also is significantly higher in invasive EOC’s than in LMP’s. These results will be confirmed in a larger cohort using an ovarian tissue/tumor microarray of 404 samples, comparing expression of full-length p170 EGFR to p110 sEGFR. Given the potential utility of p110 sEGFR as a serum biomarker in EOC patients, understanding the pattern of p110 sEGFR expression in ovarian tumors, especially in relation to p170 EGFR, is a critical avenue of investigation. (Supported by the NIH CA85133). ¹Reiter et al., 2001 Genomics 71:1. ²Baron et al., 2003 Cancer Epidemiol. Biomarkers Prev. 12:103. ³Christensen et al., 2002 Hybrid. Hybridomics 21:183.