1. ¹Leibniz Research Centre for Working Environment and Human Factors, University of Dortmund, Ardeystrae 67, Dortmund D-44139, Germany
2. ²Institute of Legal Medicine/Rudolph-Boehm-Institute of Pharmacology and Toxicology, Leipzig D-04103, Germany
3. ³Institute of Pathology, Division of Gynaecopathology, University of Leipzig, Leipzig D-04103, Germany
4. ⁴Institute of Biology I, Division of Plantphysiology, University of Leipzig, Leipzig D-04103, Germany
5. ⁵Department of Obstetrics and Gynaecology, Medical School, University of Leipzig, Semmelweisstr. 14, Leipzig D-04103, Germany
6. ⁶Department of Internal Medicine II, Max Burger Research Centre, University of Leipzig, Johannisallee 30, Leipzig D-04107, Germany
7. ⁷Department of Obstetrics & Gynaecology, Medical School, University of Mainz, Mainz D55101, Germany
8. ⁸Medical Genetics and Molecular Medicine, University of Mainz, Mainz 55101, Germany

Correspondence: Professor Dr JG Hengstler, E-mail: Hengstler@ifado.de

Revised 21 February 2008; Accepted 27 February 2008; Published online 29 April 2008.

Abstract

Trastuzumab (Herceptin) has improved therapy of breast cancer. Only patients overexpressing ERBB2 are treated with trastuzumab, whereas its use in tumours without ERBB2 expression is useless. This led to the concept that the subgroup of trastuzumab-sensitive tumours is 'ERBB2-dependent', meaning that ERBB2 signalling is indispensable for growth of these tumours. We used a mouse model that allows anhydrotetracycline (ATc)-controlled downregulation of ERBB2 in tumour tissue. ERBB2 mRNA and protein expression were downregulated below detection limit leading to a macroscopically complete tumour remission within 14 days. Tumour remission was accompanied by a strong decrease in proliferation, a moderate increase in apoptosis, as well as dephosphorylation of ERK1/2 and AKT/PKB. These data clearly indicate ERBB2 dependence. Therefore, a high sensitivity to trastuzumab may be suspected. Surprisingly, trastuzumab caused a much weaker effect compared to ATc-induced ERBB2 downregulation, although a decrease in ERBB2 membrane localisation was induced. Only a slight decrease in proliferation and a weak transient increase in apoptosis were observed. Interestingly, tumours responded to trastuzumab by a sharp fivefold increase in phosphorylated AKT/PKB as well as a 3.5- and 5.3-fold increase in AKT1 and AKT2 mRNA levels, respectively. In conclusion, 'ERBB2 dependence' is not sufficient to define trastuzumab-responsive tumours. The suboptimal effect of trastuzumab compared to the maximally possible effect induced by ATc demonstrates a high potential for improved ERBB2 blocking therapies.