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ErbB2 pathways in heart and neural diseases
Alistair N Garratt1, Cemil Ozcelik, Carmen Birchmeier
1Max-Delbrück-Centre for Molecular Medicine, Robert-Rössle-Strasse 10, Postfach 740238, 13092 Berlin, Germany.
Abstract:
The proto-oncogene ErbB2 (also known as c-neu or HER2 in humans) encodes a receptor tyrosine kinase that is frequently overexpressed in human tumors. It is the target of a novel and effective antibody-based therapy for malignant mammary tumors (trastuzumab/Herceptin). Biochemical and genetic experiments have shown that ErbB2 acts as a coreceptor for other members of the ErbB family of receptor tyrosine kinases. In particular, signals are transduced by ErbB2/ErbB4, ErbB2/ErbB3, and ErbB2/EGF receptor heteromers. ErbB2/4 and ErbB2/ErbB3 heteromers transmit neuregulin-1 signals in the developing and adult heart, and in the peripheral nervous system, respectively. Of particular medical relevance are recent findings that relied on tissue-specific mutation of ErbB2 in cardiomyocytes, which revealed an essential function of ErbB2 in normal heart physiology and demonstrated that loss of cardiac ErbB2 can cause dilated cardiomyopathy in adult mice. Thus, ErbB2 is important not only in development, but also for the correct functioning of the differentiated myocardium. The conditional ErbB2 mutant mice provide a model for the principal side effects--cardiomyopathy and heart failure--that can be observed in patients undergoing chemotherapy with Trastuzumab.
Insights
The proto-oncogene ErbB2 is crucial for normal heart function and its loss can lead to dilated cardiomyopathy. This finding is relevant to understanding chemotherapy side effects like heart failure in patients treated with trastuzumab.
Area of Science:
- Oncology
- Cardiology
- Molecular Biology
Background:
- The proto-oncogene ErbB2 (HER2) is a receptor tyrosine kinase overexpressed in human tumors and targeted by trastuzumab therapy.
- ErbB2 functions as a coreceptor, forming heteromers with other ErbB family members (ErbB4, ErbB3, EGF receptor) to transduce signals.
- ErbB2/ErbB4 and ErbB2/ErbB3 heteromers are vital for neuregulin-1 signaling in the heart and peripheral nervous system.
Purpose of the Study:
- To investigate the role of ErbB2 in normal heart physiology.
- To determine the consequences of ErbB2 loss in cardiomyocytes.
- To establish a mouse model for trastuzumab-induced cardiotoxicity.
Main Methods:
- Tissue-specific mutation of ErbB2 in cardiomyocytes of mice.
- Analysis of cardiac physiology and function in conditional ErbB2 mutant mice.
- Evaluation of ErbB2's role in differentiated myocardium.
Main Results:
- Loss of cardiac ErbB2 function in adult mice leads to dilated cardiomyopathy.
- ErbB2 is essential for normal heart physiology beyond development.
- Conditional ErbB2 mutant mice exhibit cardiomyopathy and heart failure, mirroring trastuzumab side effects.
Conclusions:
- ErbB2 plays a critical role in maintaining adult heart function.
- Cardiac ErbB2 deficiency results in dilated cardiomyopathy and heart failure.
- Conditional ErbB2 mutant mice serve as a relevant model for trastuzumab-induced cardiotoxicity.