Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy

AN Garratt, PhD a, B Erdmann, PhD a, Bernhard Pilz, M.D. b, Nina Wettschureck Ph.D. c, Stefan Britsch M.D. a, Norbert Huebner Ph.D. a, Kenneth R. Chien Ph.D. d, Carmen Birchmeier Ph.D a

a Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany b Franz-Volhard-Klinik, 13125 Berlin, Germany c University of Heidelberg, 69120 Heidelberg, Germany d University of California San Diego, Medical School, La Jolla, CA, USA

The ErbB2 (Her2) proto-oncogene encodes a receptor tyrosine kinase, which is frequently amplified and over-expressed in human tumors. ErbB2 provides the target for a novel and effective antibody-based therapy (Trastuzumab/Herceptin), which is used generally in combination with cytostatic agents for treatment of patients with malignant mammary carcinomas. However, a proportion of patients treated with Trastuzumab develop cardiomyopathies. The side effect was augmented in patients with a previous history of cardiac dysfunction, or those treated with Trastuzumab and anthracyclines. Gene ablation studies have previously demonstrated that the ErbB2 receptor, together with its co-receptor ErbB4 and the ligand Neuregulin-1, are essential for a normal development of the heart ventricle. We use here Cre-loxP technology to mutate ErbB2 specifically in cardiomyocytes. Conditional mutant mice develop a severe dilated cardiomyopathy, with signs of cardiac dysfunction appearing by the second postnatal month. We infer that signaling from the ErbB2 receptor, which is enriched in T-tubules in cardiomyocytes, is crucial to the function of the adult heart. Conditional ErbB2 mutants provide an attractive animal model of dilated cardiomyopathy. In particular, these mutants will allow a rigorous assessment of the adverse effects of anti-ErbB2 antibodies on cardiac function.

KEY WORDS: Cre-lox Trastuzumab, Herceptin t-tubule.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Novel Therapies, Part 2.