Enhanced c-erbB-2/neu Expression in Human Ovarian Cancer Cells Correlates with More Severe Malignancy That Can Be Suppressed by EIA1

Amplification or overexpression of t-erbß-2/neu protooncogene, or both, occur frequently in many different types of human cancers and have been shown to correlate with decreased survival in ovarian cancer pa tients. We have previously found that the ovarian carcinoma cell line SK-OV-3 overexpresses c-erbß-2/neu mRNA. To further study the bio logical effect of c-erbB-2/neu overexpression in SK-OV-3 cells, we in jected such cells i.p. into female nu/nu mice and found that this cell line forms extensive abdominal tumors and ascites. From the ascites in an injected mouse, we established the SKOV3.ipl cell line and found that it expressed 2-fold more c-erfrß-2/neu-encoded pl85 proteins than the pa rental SK-OV-3 cells. When transformation phenotypes of SK-OV-3 and SKOV3.ipl cells were compared, SKOV3.ipl cells showed higher cell growth and DNA synthesis rates, formed more colonies in soft agar, pro duced larger s.c. tumors, and resulted in shorter survival of nu/nu mice after i.p. injection. These data indicate that the level of c-erbß-2/neu overexpression may correlate with the degree of malignancy in these ovarian carcinoma cells. Since we had previously shown that the adenovirus 5 EIA gene product can suppress transformation and metastatic prop erties induced by mutation-activated rat neu oncogene in mouse embryo fibroblast cells, we further examined whether EIA can abrogate malig nancy in c-<rAB-2/neu-overexpressing human ovarian cancer cells. We introduced the EIA gene into c-fréB-2/neu-overexpressing SKOV3.ipl cells and found that the ElA-expressing ovarian cancer cell lines had decreased c-erbB-2/neu-encoded pl85 expression and reduced malignancy, including a decreased ability to induce tumors in nu/nu mice. Therefore, we concluded that EIA is a tumor suppressor gene for c-erbR-2/neuoverexpressing human ovarian cancer cells and may be useful in devel oping therapeutic reagents for these human cancers.