THE ROLE OF EPIDERMAL GROWTH FACTOR RECEPTOR 2 OVEREXPRESSION ON ATTENUATING REACTIVE OXYGEN SPECIES IN THE HEART

ErbB2;heart;glutathione peroxidase;reactive oxygen species;mitochondria;Abl kinases;not listed

Belmonte, Frances RabusaCulotta, Valeria L. ;

Johns Hopkins University

关键词: ErbB2;    heart;    glutathione peroxidase;    reactive oxygen species;    mitochondria;    Abl kinases;    not listed;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/37882/BELMONTE-DISSERTATION-2014.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Current statistics for the incidence of breast cancer reveal that it is the most common form of cancer and leading cause of death from cancer among women worldwide. In the US, breast cancer follows lung cancer as the second largest cause of cancer mortality and is the most common type of cancer in American women. Approximately 15-20% of breast cancers are characterized as HER2/neu/ErbB2 (epidermal growth factor receptor 2)-positive. The combination of doxorubicin and the ErbB2 inhibitor Herceptin/trastuzumab is efficacious against ErbB2-overexpressing breast cancer but has been shown to cause cardiotoxicity and has been linked to an increased risk for developing cardiac failure. The following chapters of this dissertation will explore the intricacies of ErbB2 tyrosine kinase signaling and the essential roles of ErbB2 in cardiac development and function. For our studies we employed a transgenic murine model of cardiac-specific ErbB2 overexpression developed in our lab that has concentric cardiac hypertrophy that does not progress to heart failure. Since oxidative stress mediates the transition from cardiac hypertrophy to heart failure, we sought to investigate the underlying mechanisms of ErbB2 overexpression on redox signaling pathways involved in antioxidant protection against reactive oxygen species (ROS). Indeed, hearts from the ErbB2 transgenic (ErbB2tg) mice and their cardiac mitochondria have lower levels of ROS. We proposed that ErbB2 regulates the Abelson nonreceptor tyrosine kinases to subsequently activate glutathione peroxidase (GPx) and reduce ROS levels. In vitro models of ErbB2 overexpression and abrogration in the H9c2 rat cardiomyoblast cell line were developed to assess these associations. Studies with neonatal cardiomyocytes suggest that GPx activity in the ErbB2tg mice is dependent upon the hypertrophic phenotype that is conspicuously absent in the H9c2 cells.Using the ErbB2tg model we identified a unique multi-protein signaling pathway that supports a cardioprotective role of ErbB2 in reducing ROS levels in the heart. It is possible that ErbB2 inhibitors can effectively block these components that are necessary for preventing adverse cardiac outcomes. The ErbB2tg mouse model is a valuable tool for the discovery of novel mechanisms and signaling pathways that have potential translational significance for cardiovascular studies and cancer biology.