Elevated serum levels of a c-erbB-2 oncogene product in ovarian cancer patients and in pregnancy

Abstract

Amplification of the proto-oncogene c-erbB-2 (HER-2/neu) has been shown to be a prognostic marker in ovarian cancer. In order to obtain further information on the biological role of the c-erbB-2 gene product p185 it is necessary to quantify expression levels. In this study we evaluated an enzyme-linked immunosorbent assay (ELISA) for the extracellular domain of p185 to determine whether a soluble oncoprotein fragment can be detected in the serum of ovarian cancer patients and in the serum of pregnant women. Sera from 199 women (57 previously untreated ovarian cancer patients, 62 pregnant women and 80 healthy controls) were assayed in a sandwich ELISA utilizing two mouse monoclonal antibodies. To study c-erbB-2 overexpression in ovarian cancer tissue samples we have used an immunohistochemical technique involving a monoclonal antibody specifically reactive with the external domain of the protein p185. The mean serum value for the normal controls was 1203 HNU/ml with a standard deviation (SD) of 279 HNU/ml and a range of 595-1947 HNU/ml. We chose a level of 1761 HNU/ml (2 SD above the mean) as a cut-off to distinguish individuals with elevated levels. The ovarian cancer patients' serum values ranged from 526 to 16,332 HNU/ml. Immunohistochemically detectable p185 was noted in 8 of 57 ovarian cancer patients. The oncoprotein fragment levels in the sera from these 8 patients ranged from 878 to 16,332 HNU/ml. Of 8 patients with p185 overexpression in their tumors, 4 had elevated serum levels. In the sera from the 49 cancer patients without overexpression the values were distributed in the range 526-2892 HNU/ml. There was no association between serum oncoprotein fragment levels and tumor stage, histological type or grading. Serum concentrations of the p185 fragment in pregnancy ranged from 612 to 3265 HNU/ml. The highest levels were found in the third trimester. The results of the present study raise the possibility that the soluble c-erbB-2 protein level in serum is an indicator for cell proliferation and therefore deserves further evaluation as a diagnostic tool in ovarian cancer patients and pregnancy.