BACKGROUND: Angiogenesis and haemostasis are closely linked within tumours with many haemostatic proteins regulating tumour angiogenesis. Indeed we previously identified a fragment of human fibrinogen, fibrinogen E-fragment (FgnE) with potent antiangiogenic properties in vitro and cytotoxic effects on tumour vessels in vivo. We therefore investigated which region of FgnE was mediating vessel cytotoxicity. METHODS: Human dermal microvascular endothelial cells (ECs) were used to test the efficacy of peptides derived from FgnE on proliferation, migration, differentiation, apoptosis and adhesion before testing the efficacy of an active peptide on tumour vasculature in vivo. RESULTS: We identified a 20-amino-acid peptide derived from the b chain of FgnE, b43 -63, which had no effect on EC proliferation or migration but markedly inhibited the ability of activated ECs to form tubules or to adhere to various constituents of the extracellular matrix -collagen IV, fibronectin and vitronectin. Furthermore, our data show that b43 -63 interacts with ECs, in part, by binding to a v b 3 , so soluble a v b 3 abrogated b43 -63 inhibition of tubule formation by activated ECs. Finally, when injected into mice bearing tumour xenografts, b43 -63 inhibited tumour vascularisation and induced formation of significant tumour necrosis. CONCLUSIONS: Taken together, these data suggest that b43 -63 is a novel anti-tumour peptide whose anti-angiogenic effects are mediated by a v b 3 .

Background Epidemiological studies have shown that only about 20% of the familial clustering of breast cancer is explained by the known highly penetrant mutations in BRCA1 and BCRA2. We have set out to search for the genes for the remaining 80%. Twin studies indicate a predominant role of shared genes rather than a shared environment; the patterns of occurrence of breast cancer in families are consistent with a major polygenic component. Methods We have assembled a population based set of 5,000 breast cancer cases and 5,000 controls from the East Anglian population. We have simple clinical and epidemiological information, including family history, and samples of blood and paraffin embedded tumour. We have used association studies based on single nucleotide polymorphisms, first with candidate genes and then in a genome-wide scan of 266,000 single nucleotide polymorphisms, to search for the putative predisposing genes. We have as yet searched only for common variants (frequency >5%). Results We have modelled the effects of polygenic predisposition in the East Anglian population, and have shown that the model predicts a wide distribution of individual risk in the population, such that half of all breast cancers may occur in the 12% of women at greatest risk. Both the candidate gene-based and genome-wide scans have provided provisional identification of a number of novel susceptibility genes, and these are currently being confirmed by a worldwide consortium of independent laboratories totalling 20,000-plus cases and controls. No single gene so far identified contributes more than 2% of the total inherited component, consistent with a model in which susceptibility is the result of a large number of individually small genetic effects. S2 Translating breast cancer research into clinical practice-new approaches and better outcomes