Abstract
Amplification of the gene encoding the ErbB2 (Her2/neu) receptor tyrosine kinase is critical for the progression of several forms of breast cancer. In a large-scale clinical trial, treatment with Herceptin (trastuzumab), a humanized blocking antibody against ErbB2, led to marked improvement in survival. However, cardiomyopathy was uncovered as a mitigating side effect, thereby suggesting an important role for ErbB2 signaling as a modifier of human heart failure. To investigate the physiological role of ErbB2 signaling in the adult heart, we generated mice with a ventricular-restricted deletion of Erbb2. These ErbB2-deficient conditional mutant mice were viable and displayed no overt phenotype. However, physiological analysis revealed the onset of multiple independent parameters of dilated cardiomyopathy, including chamber dilation, wall thinning and decreased contractility. Additionally, cardiomyocytes isolated from these conditional mutants were more susceptible to anthracycline toxicity. ErbB2 signaling in cardiomyocytes is therefore essential for the prevention of dilated cardiomyopathy.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 459-465 |
| Number of pages | 7 |
| Journal | Nature Medicine |
| Volume | 8 |
| Issue number | 5 |
| DOIs | |
| State | Published - 2002 |
Funding
Acknowledgments We thank K. Campbell and Y. Kobayashi for antibodies against cytoskeletal proteins; R. Gottlieb and R. Sayen for analysis of the function of mitochondria; J. Adams for adenoviral Bcl-xL; Ma. Hoshijima for help with adenovirus injection; and N. Dalton for expertise in echocardiography. The work was supported by NIH grants and The Jean Le Ducq Foundation (to K.R.C. and K.F.L.) and support from an AHA endowed chair and Genentech, Inc (to K.R.C.). S.A.C. is a Markey Predoctoral Fellow and recipient of an award from the Chapman Foundation. K.F.L. is a Pew Scholar.
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology
