Perspektiven HER-2 blockierender Therapiestrategien im Mausmodell: Rasche Tumorremission in Abhängigkeit vom Tumorstadium, aber keine dauerhafte Heilung

Purpose: HER-2 blocking strategies, for instance with trastuzumab (Herceptin®), have been successfully used in therapy of breast cancer. To study molecular mechanisms and the efficiency of HER-2 blocking therapies we established a mouse tumor model that allows switching-off of HER-2 expression in tumor tissue. Material and Methods: NIH3T3 cells conditionally expressing HER-2 by the TET-OFF system (NIH3T3-HER-2 cells) were subcutaneously injected into the dorsal skin of nude mice. These cells allowed switching-off of HER-2 expression by exposure to anhydrotetracycline. We examined the influence of HER-2 down-regulation on tumor volume of subcutaneously growing tumors in nude mice. Tumor development was studied by magnetic resonance imaging. HER-2 expression was quantified by Western Blot analysis. Results: Eight to ten days after injection of 7 × 10 6 NIH3T3-HER-2 cells small subcutaneously growing tumors became visible. A surprisingly efficient tumor remission was observed already 7 days after switching-off of HER-2 expression: mice with initial tumor volumes of 0.8, 1.2, 3.9 and 14.9 cm 3 showed a decrease in tumor volumes to 1.9, 11.8, 11.3 and 25.8%, respectively, compared to the respective volumes before anhydrotetracycline administration. In contrast, a steady increase in tumor volume was observed for mice not exposed to anhydrotetracyclin. Conclusion: Switching-off of HER-2 expression causes a strong remission already after 7 days. Interestingly, the extent of tumor remission depends on initial tumor size, whereby a stronger remission can be achieved for smaller tumors. Our data support clinical studies testing HER-2 blocking strategies as adjuvant therapy for early breast cancer.