Crone Steven A, Zhao You-Yang, Fan Lian, Gu Yusu, Minamisawa Susumu, Liu Yang, Peterson Kirk L, Chen Ju, Kahn Ronald, Condorelli Gianluigi, Ross John, Chien Kenneth R, Lee Kuo-Fee
The Salk Institute, La Jolla, California, USA.
Nat Med. 2002 May;8(5):459-65. doi: 10.1038/nm0502-459.
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.
编码表皮生长因子受体2（ErbB2，即Her2/neu）受体酪氨酸激酶的基因扩增对多种形式乳腺癌的进展至关重要。在一项大规模临床试验中，使用赫赛汀（曲妥珠单抗）进行治疗，这是一种针对ErbB2的人源化阻断抗体，可显著提高生存率。然而，发现心肌病是一种减轻的副作用，从而表明ErbB2信号传导作为人类心力衰竭的调节因子具有重要作用。为了研究ErbB2信号传导在成年心脏中的生理作用，我们构建了心室限制性缺失Erbb2的小鼠。这些ErbB2缺陷型条件突变小鼠存活且未表现出明显的表型。然而，生理分析揭示了扩张型心肌病多个独立参数的出现，包括心室扩张、室壁变薄和收缩力下降。此外，从这些条件突变体中分离出的心肌细胞对蒽环类药物毒性更敏感。因此，心肌细胞中的ErbB2信号传导对于预防扩张型心肌病至关重要。
