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

Cemil Ozcelik1, Bettina Erdmann, Bernhard Pilz

  • 1Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.

Proceedings of the National Academy of Sciences of the United States of America
|June 20, 2002
PubMed

Insights

Targeting the ErbB2 (Her2) receptor is key for cancer therapy, but can cause heart problems. This study shows ErbB2 signaling is crucial for adult heart function, offering insights into cardiac side effects.

Area of Science:

  • Cardiovascular Biology
  • Oncology
  • Molecular Biology

Background:

  • The ErbB2 (Her2) proto-oncogene is a receptor tyrosine kinase overexpressed in human tumors.
  • ErbB2 is the target for Trastuzumab (Herceptin), an antibody therapy for mammary carcinomas.
  • Trastuzumab treatment can lead to cardiomyopathies, especially when combined with chemotherapy.

Purpose of the Study:

  • To investigate the role of ErbB2 in adult heart function.
  • To develop a mouse model for studying ErbB2-related cardiac dysfunction.
  • To understand the molecular mechanisms behind adverse effects of anti-ErbB2 antibodies on the heart.

Main Methods:

  • Utilized Cre-loxP technology for specific mutation of ErbB2 in ventricular cardiomyocytes.
  • Generated conditional mutant mice lacking functional ErbB2 in heart ventricles.
  • Assessed cardiac function and morphology in mutant mice.

Main Results:

  • Conditional ErbB2 mutant mice developed severe dilated cardiomyopathy.
  • Cardiac dysfunction was observed by the second postnatal month in mutant mice.
  • ErbB2 signaling, particularly in cardiomyocyte T-tubules, is essential for adult heart function.

Conclusions:

  • Conditional ErbB2 mutant mice serve as a valuable model for dilated cardiomyopathy.
  • This model allows for rigorous assessment of ErbB2's role in cardiac health.
  • Findings provide insight into the molecular basis of cardiac adverse effects from anti-ErbB2 therapies.

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