Recent studies have led to the recognition of the epidermal growth factor receptor HER3 as a key player in cancer, and consequently this receptor has gained increased interest as a target for cancer therapy. We have previously generated several Affibody molecules with subnanomolar affinity for the HER3 receptor. Here, we investigate the effects of two of these HER3-specific Affibody molecules, ...

The ErbB3/4 ligand heregulin (HRG) profoundly affects cell growth and differentiation, but its mechanism of action is poorly understood. Ebp1, a protein isolated by its binding to ErbB3, inhibits cell growth and represses transcription of E2F-regulated cell cycle genes. Since Ebp1 shares 38% identity with a Schizosaccharomyces pombe DNA-binding protein, we postulated that Ebp1 could bind E2F co...

A significant number of HER-2 amplified breast cancers is effectively treated by trastuzumab and further shows receptor-enhanced chemosensitivity. Recent studies have postulated transactivation of HER-2 also in tumors expressing phosphorylated/activated HER-2 (pHER-2) and of the HER-3/HER-4 ligand heregulin (HRG), independent of HER-2 amplification. As a consequence, a subset of tumors without ...

Heregulin (HRG) activates ErbB2-ErbB3 heterodimers thereby stimulating many cellular responses, including motility. Memo and PLCgamma1 interact with ErbB2 autophosphorylation sites and are essential for HRG-induced chemotaxis. By tracing HRG-stimulated cell migration in Dunn chambers, we found that Memo- or PLCgamma1 knockdown (KD) strongly impairs cell directionality. Memo has no obvious enzym...

The angiogenic switch is a promising therapeutic target in cancer. Work by our laboratory and others has described an important endogenous anti-angiogenic pathway mediated by interactions of CD36, a receptor on microvascular endothelial cells, with proteins containing thrombospondin (TSP) type I repeat domains (TSR). Recent studies revealed that circulating Histidine Rich Glycoprotein (HRG) inh...

Human epidermal growth factor receptor-3 (HER3) is a member of the type I receptor tyrosine kinase family. Several members of this family are overexpressed in various carcinomas. Specifically, HER2 is found to be overexpressed in 20-30% of breast cancers. In contrast to epidermal growth factor receptor or HER2, the kinasedeficient HER3 self-associates readily at low nanomolar concentrations and...

Trial ALL-BFM 90 was designed to improve outcome in patients with childhood acute lymphoblastic leukemia (ALL) by using a reduced treatment regimen. Patients were stratified into a standard-risk group (SRG), a medium-risk group (MRG), both defined by adequate early treatment response; and a high-risk group (HRG), defined by inadequate response to the cytoreductive prednisone prephase, induction...

Migration/invasion is involved in the multiple steps of metastasis, resulting in a poor prognosis of breast cancer. (-)-Epigallocatechin-3-gallate (EGCG) in green tea inhibits the metastasis of some cancer cell lines. Cell migration/invasion assays using Boyden chambers demonstrated that (-)-epigallocatechin (EGC), another green tea catechin, inhibited heregulin-beta1 (HRG)-induced migration/in...

Extensive angiogenesis, formation of new capillaries from pre-existing blood vessels, is an important feature of malignant glioma. Several antiangiogenic drugs targeting vascular endothelial growth factor (VEGF) or its receptors are currently in clinical trials as therapy for high-grade glioma and bevacizumab was recently approved by the FDA for treatment of recurrent glioblastoma. However, the...

ErbB tyrosine kinase receptors mediate mitogenic signal cascade by binding a variety of ligands and recruiting the different cassettes of adaptor proteins. In the present study, we examined heregulin (HRG)-induced signal transduction of ErbB4 receptor and found that the phosphatidylinositol 3'-kinase (PI3K)-Akt pathway negatively regulated the extracellular signal-regulated kinase (ERK) cascade...