oa Editorial: Targeting Neuregulin1 and HER Receptor Tyrosine Kinases for Therapy of Breast Cancer and Heart Failure

The Neuregulin1 proteins and HER receptor tyrosine kinases are pivotal for function and disease development of multiple organ systems, including breast cancer and the heart [1, 2]. The HER2 receptor is mutated or overexpressed in about 20-30% of metastatic breast cancers [3]. Therefore, it is a major drug target of breast cancer therapy. Trastuzumab, a monoclonal antibody that directly binds and blocks the HER2 receptor, is among the first drugs approved by the US Food and Drug Administration for targeted cancer therapy, which proven to be effective for improving the overall survival of breast cancer patients [4]. However, Trastuzumab can cause severe heart failure in patients, especially when used in combination with the chemotherapy drug doxorubicin [4]. Clinical studies show that the New York Heart Association class III/IV heart failure is significantly increased in breast cancer patients treated concurrently with Trastuzumab and doxorubicin compared to doxorubicin alone (16 vs. 4 %), suggesting the HER2 receptor is necessary for protecting the heart from doxorubicin-induced cardiotoxicity [4]. This clinical finding led to a decade of vigorous research on the HER signaling in heart failure, as well as the identification of Neuregulin1 as a cardio-protective factor [5-10]. Clinical trials are ongoing to test the therapeutic effects of using recombinant Neuregulin1 for the treatment of heart failure [11]. With the success of inhibiting the HER2 signals in cancer and using Neuregulin1 for heart failure, major clinical challenges remain which are: how to inhibit the HER signaling for cancer therapy while sparing the heart, and whether Neuregulin1 proteins can be safely used in patients without exacerbating the existing cancer burden or increasing the risk of cancer. In this issue, scientists from both the oncology and cardiology fields are getting together to review the current knowledge of the Neuregulin1-HER signaling in breast cancer and the heart. In the paper “Neuregulin Signaling in Pieces – Evolution of the Gene Family”, Mark Marchionni utilizes gene structure and protein sequence searches and alignments, as well as construction of phylogenetic tree to illustrate how Neuregulins and HER receptor tyrosine kinases evolve during evolution to form a complex signaling network that is currently known. In the paper “Heregulin in Breast Cancer: Old Story, New Paradigm”, Ruth Lupu et al. review Neuregulins’ biological role in the development, progression and maintenance of breast cancer. In the paper “Breast Cancer Biomarkers: Risk Assessment, Diagnosis, Prognosis, Prediction of Treatment Efficacy and Toxicity, and Recurrence”, Adedayo Onitilo et al. review the biomarker development for assisting breast cancer diagnosis, prediction of prognosis, therapeutic response and toxicity. In the paper “Cardiovascular Effects of Neuregulin1-1/ErbB Signaling: Role in Vascular Signaling and Angiogenesis”, Kerry Russell et al. review the role of Neuregulin-HER signaling in endothelial cell angiogenesis, vascular smooth muscle cell proliferation and migration, and maintenance of vascular structure and function. This paper also reviews the cross-talk between cardiac endothelial cells and cardiomyocytes, Neuregulin1 and VEGF signaling, as well as Neuregulin1 and inflammatory cytokines. In the paper “The Developing Role of Neuregulin1 in Cardiac Regenerative Stem Cell Therapy”, James Morgan et al. review the findings of using Neuregulin1 proteins to direct stem cell differentiation into the cardiac lineage in cell culture and discuss the potential use of Neuregulin1 to improve the therapeutic efficacy of stem cell therapy for heart failure. In the paper “Anti-HER2 Cancer Therapy and Cardiotoxicity”, Xinhua Yan et al. review the current anti-HER2 therapies, the preclinical and clinical data on cardiotoxicity induced by anti-HER2 therapy and the mechanisms of how HER2 signaling protects the heart from stress. In the paper “Tumor Dormancy and the Angiogenic Switch: Possible Implications of Bone Marrow-Derived Cells”, Nava Almog et al. review the molecular and cellular regulators, including growth stimulatory signals for angiogenic switch in dormant tumors. In the paper “Mathematical Modeling of Tumor Growth and Treatment”, Heiko Enderling et al. discuss how to use mathematic modeling to simulate the dynamic biological process of tumor growth, tumor-host interactions and to predict treatment response.