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Switching Off HER-2/neu in a Tetracycline-Controlled Mouse Tumor Model Leads to Apoptosis and Tumor-Size-Dependent Remission¹

Institute of Toxicology [I. B. S., S. Ge., C. K. H., F. O.], Departments of Radiology [A. H., J. H., W. G. S., M. T.], Hematology [U. W., B. S.], and Gynaecology [B. T.], University of Mainz, 55131 Mainz; Baxter Oncology GmbH, 60314 Frankfurt [S. Gi.]; Atlanta Pharma, 78467 Konstanz [T. B.]; Zentaris, 60314 Frankfurt [S. B.]; Urological Clinic and Polyclinic [W. B.], Children’s Hospital [C. S., D. P., T. T., B. Z.], and Institute of Pathology [H. A. L.], University of Mainz, 55131 Mainz; Institute of Legal Medicine and Rudolf-Boehm Institute of Pharmacology and Toxicology, Center for Toxicology, University of Leipzig, 04107 Leipzig [J. G. H.], Germany

Overexpression of the receptor tyrosine kinase HER-2/neu is associated with poor prognosis in patients with breast and ovarian cancer. Recent excitement has surrounded the therapeutic effects of HER-2-blocking therapy strategies and has rekindled interest on the molecular mechanisms of HER-2/neu in tumor biology. To study the role of HER-2/neu overexpression in vivo, we used a murine fibroblast cell line (NIH3T3-her2) conditionally expressing human HER-2/neu under control of a tetracycline-responsive promoter. Expression of HER-2 could be down-regulated below detection limit (>625-fold dilution) by exposure of NIH3T3-her2 cells to anhydrotetracycline (ATc). Subcutaneous injection of NIH3T3-her2 cells into nude mice resulted in rapid tumor growth. Mice with mean tumor volumes of 0.2, 0.8, 1.9, and 14.9 cm³ were treated daily with 10 mg/kg ATc to switch off HER-2/neu expression, producing reductions in tumor size of 100, 98.1, 81.4, and 74.2%, respectively, by 7 days after onset of ATc administration (P = 0.005, Kruskal–Wallis test). Different long-term effects of HER-2 down-regulation were observed when mice with small (0.2 cm³; n = 7), intermediate (0.8–1.2 cm³; n = 10) and large (1.9 cm³; n = 11) tumors received ATc for up to 40 days. Complete remission was observed for 100, 40, and 18% of the small-, intermediate-, and large-sized tumors, respectively (P = 0.003). However, after 20–45 days of ATc administration, recurrent tumor growth was observed for all mice, even in those with previous complete remissions. The time periods for which mean tumor volume could be suppressed to volumes <0.1 cm³ under ATc administration were 34, 22, 8, and 0 days for tumors with initial volumes of 0.2, 0.8, 1.9 and 14.9 cm³, respectively (P = 0.005, Kruskal–Wallis test). Interestingly, HER-2 remained below the detection limit in recurrent tumor tissue, suggesting that initially HER-2-dependent tumors switched to HER-2 independence. The "second hits" leading to HER-2-independent tumor growth have not yet been identified. The rapid regression of tumors after down-regulation of HER-2 was explained by two independent mechanisms: (a) a block in cell cycle progression, as evidenced by a decrease in Ki-67 antigen expression from 40% before ATc treatment to 8.3% after 7 days of ATc treatment; and (b) induction of apoptosis as demonstrated by caspase-3 activation and by the terminal deoxynucleotidyltransferase (Tdt)-mediated nick end labeling assay (TUNEL). In conclusion, we have shown that switching off HER-2 may disturb the sensitive balance between cell proliferation and cell death, leading to apoptosis and tumor remission. Tumor remission was dependent on the volume of the tumors before down-regulation of HER-2/neu.

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