The effect of HER-2/neu overexpression on chemotherapeutic drug sensitivity in human breast and ovarian cancer cells

• Published in: Oncogene Vol. 15; no. 5; pp. 537 - 547
• Main Authors: PEGRAM, M. D, FINN, R. S, ARZOO, K, BERYT, M, PIETRAS, R. J, SLAMON, D. J
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 31.07.1997; Nature Publishing Group
• Subjects: Animals; Antineoplastic Agents - pharmacology; Biological and medical sciences; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Cell physiology; Cell proliferation; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transplantation; Chemotherapy; Dose-Response Relationship, Drug; Drug resistance; Drug Resistance, Neoplasm - genetics; ErbB-2 protein; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Neoplastic; Genetic Vectors; Humans; Mice; Mice, Nude; Molecular and cellular biology; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - genetics; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Recombinant Proteins - drug effects; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Retroviridae - genetics; Statistical analysis; Transfection; Transplantation, Heterologous; Tumor Cells, Cultured; Tumors; Xenografts; Antineoplastic agent; Human; Gene overexpression; Gene expression; Female genital diseases; Resistance; Mammary gland diseases; Ovarian diseases; Ovary; Chemotherapy; Cell line; C-Onc gene; Chemosensitivity; Tumor; Mammary gland; Biological receptor
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1201222

Recent studies indicate that oncogenes may be involved in determining the sensitivity of human cancers to chemotherapeutic agents. To define the effect of HER-2/neu oncogene overexpression on sensitivity to chemotherapeutic drugs, a full-length, human HER-2/neu cDNA was introduced into human breast and ovarian cancer cells. In vitro dose-response curves following exposure to 7 different classes of chemotherapeutic agents were compared for HER-2- and control-transfected cells. Chemosensitivity was also tested in vivo for HER-2- and control-transfected human breast and ovarian cancer xenografts in athymic mice. These studies indicate that HER-2/neu overexpression was not sufficient to induce intrinsic, pleomorphic drug resistance. Furthermore, changes in chemosensitivity profiles resulting from HER-2/neu transfection observed in vitro were cell line specific. In vivo, HER-2/neu-overexpressing breast and ovarian cancer xenografts were responsive to different classes of chemotherapeutic drugs compared to control-treated xenografts with no statistically significant differences between HER-2/neu-overexpressing and nonoverexpressing xenografts. We found no instance in which HER-2/neu-overexpressing xenografts were rendered more sensitive to chemotherapeutic drugs in vivo. HER-2/neu-overexpressing xenografts consistently exhibited more rapid regrowth than control xenografts following initial response to chemotherapy suggesting that a high rate of tumor cell proliferation rather than intrinsic drug resistance may be responsible for the adverse prognosis associated with HER-2/neu overexpression in human cancers.