Activation of ERBB Receptors by Endothelial Neuregulin-1 Links Heart Failure to Cancer.

Recent clinical studies indicate that patients with heart failure develop cancer more frequently than patients of the same age without heart failure, indicating that heart failure could induce cancer growth. Recent experiments in animals confirmed that mice with heart failure develop more aggressive forms colon or breast cancer than mice without heart failure. The mechanisms underlying these exciting discoveries have not been determined, yet. Research into these mechanisms, however, is highly relevant, because it could provide novel insights in the pathophysiology of both disorders. The central hypothesis of the current project is that neuregulin-1 (NRG1) links heart failure to cancer. NRG1 is a endothelial-derived growth factor that is produced during heart failure and that has cardioprotective properties. NRG1 is the natural ligand of ERBB receptors—ERBB2, ERBB3, and ERBB4—which are expressed at different levels in cancer cells, and which are known as oncogenes. Blocking antibodies against ERBB2 and ERBB3 are currently used as anti-cancer drugs. We will test this hypothesis in mouse models of colorectal and breast cancer. Heart failure will be induced by ligation of a coronary artery, inducing a myocardial infarction. The role of NRG1 will be evaluated with transgenic knockout technology. We will also test the cardioprotective and pro-carcinogenic effects of administered NRG1 and specific ERBB4 agonists in these mouse models. NRG1 and ERBB4 agonists are in development for the treatment of heart failure. This project is scientifically and clinically novel for a number of reasons: it links pathophysiology of cancer to the pathophysiology of heart failure and circulatory failure. It is also important for the development of novel ERBB-based drugs for the treatment of heart failure. It will help in differentiating the growth stimulating effects of NRG1 or specific ERBB4 agonists, regardless of their cardioprotective properties.

Keywords:NEUREGULIN-1, CANCER, HEART FAILURE

Disciplines:Cardiology, Cancer biology, Non-clinical studies