Contribution of c-erbB-2 and topoisomerase IIα to chemoresistance in ovarian cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 59; no. 13; pp. 3206 - 3214
• Main Authors: HENGSTLER, J. G, LANGE, J, KETT, A, DORNHÖFER, N, MEINERT, R, ARAND, M, KNAPSTEIN, P. G, BECKER, R, OESCH, F, TANNER, B
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.07.1999
• Subjects: Biological and medical sciences; Female genital diseases; Gynecology. Andrology. Obstetrics; Medical sciences; Tumors; Antineoplastic agent; Prognosis; Gene product; Toxicity; Tumoral tissue; Ovary; Isomerases; Negative therapeutic reaction; Tumor cell; Platinum II Complexes; Human; DNA topoisomerase (ATP-hydrolysing); Enzyme; Treatment efficiency; Etoposide; Enzyme inhibitor; Malignant tumor; Gene expression; In vitro; Cisplatin; Female genital diseases; Podophyllotoxine derivatives; Ovarian diseases; In vivo; Chemotherapy; Cyclophosphamide; Oxazaphosphinane derivatives; Treatment; C-Onc gene; Nitrogen mustard; Carboplatin; Novobiocin; Predictive factor
• ISSN: 0008-5472; 1538-7445

Overexpression of the c-erbB-2 (HER-2/neu) oncogene, which encodes a transmembrane receptor tyrosine kinase, has been shown to be associated with poor prognosis in ovarian and breast cancer. Recent studies indicate that c-erbB-2 may also be involved in determining the chemosensitivity of human cancers. In the present study, we examined the role of c-erbB-2 for chemoresistance in ovarian cancer. Overexpression of c-erbB-2 mRNA in tumor tissue was associated with a shorter survival of patients with primary ovarian cancer (P = 0.0001; n = 77) and was an independent prognostic factor in the proportional-hazard model adjusted for International Federation of Gynecologists and Obstetricians stage, residual disease, chemotherapy, and age (P = 0.035). A significant association between expression of c-erbB-2 mRNA and survival was obtained for the subgroup of patients who received a standard chemotherapy with carboplatin or cisplatin and cyclophosphamide (P = 0.0003), whereas only a nonsignificant trend was observed for patients who did not receive a standard chemotherapy (P = 0.124). In addition, the application of a standard chemotherapy improved the survival of patients with relatively low c-erbB-2 expression (P = 0.013) but not of patients with overexpression of c-erbB-2 (P = 0.359). Expression of c-erbB-2 mRNA correlated with expression of topoisomerase II alpha mRNA determined by a reverse semiquantitative PCR technique (P = 0.009), whereas expression of c-erbB-2 and topoisomerase II beta mRNA did not correlate (P = 0.221). To examine the hypothesis that coamplified and/or coregulated topoisomerase II alpha contributes to the resistance of c-erbB-2-overexpressing carcinomas, we established a chemosensitivity assay using primary cells from an ovarian carcinoma that overexpressed both c-erbB-2 and topoisomerase II alpha . The combination of carboplatin with nontoxic concentrations of the topoisomerase II inhibitors etoposide or novobiocin enhanced the toxicity of carboplatin. In contrast, the tyrosine kinase inhibitor emodin exhibited no chemosensitizing effect in cells of this individual carcinoma. In conclusion, overexpression of c-erbB-2 was associated with poor prognosis and poor response to chemotherapy. The data suggest that topoisomerase II alpha , which correlates with c-erbB-2 expression, contributes to the resistance of c-erbB-2-overexpressing carcinomas.