title: Hepatocyte growth factor/scatter factor and c-met ligand-receptor in human breast cancer
Creators: name: Nagy, Janos
Publisher: name: University of Glasgow
Year: 2000
Subjects: subject: Molecular biology, oncology, breast, cancer, hepatocyte growth factor, receptor-ligand complexes.

description: HGF/SF-c-met is involved in stromal-epithelial regulation of cellular processes such as growth, dissociation, motility and invasiveness in epithelial cells 6313 and angiogenesis in endothelial cells248. When coordinated they appear to play an important role in the morphogenesis of epithelial tissues There is increasing evidence that HGF/SF-c-met is an essential regulating component of breast duct development 13,208,276,334. Aberrant expression of HGF/SF-c-met may therefore be involved in biological mechanisms that promote invasion and metastasis in human cancers. Loss of heterozygosity (LOH) at the c-met locus in breast cancer patients has been associated with disease-relapse and reduced survival16. The aims of this thesis were: 1. To investigate the frequency and significance of LOH of c-met in patients with breast cancer. 2. To investigate HGF/SF and c-met expression in patients with breast cancer. 3. To investigate the relationship of HGF/SF to tumour proliferation and angiogenesis in patients with breast cancer. Investigation on frequency of loss of heterozygosity of the c-met proto-oncogene in human breast cancer Aberrant HGF/SF-c-met function in breast cancer was first suggested by the observation of a high frequency of LOH at 7q31 (the c-met locus) in human breast cancer patients16. In this study we examined blood DNA derived from 111 patients with primary breast cancer using the pMet H probe by Southern blotting. Of the 111 patients, 52 patients were heterozygous for the Taq 1 restriction fragment length polymorphism (RFLP) of 7.5 and 4.0 kb. Tumour DNA from these patients were then analysed for LOH at 7q31. Complete LOH at 7q31 was observed in 4% of cases only. The results of this study failed to confirm the reported high frequency of LOH of c-met and do not support the presence of a tumour suppressor gene at 7q31 in human breast cancer. HGF/SF-c-met ligand receptor system in human breast cancer In this study a statistical association between HGF/SF and c-met in relation to disease- relapse in patients with primary breast cancer was demonstrated. Furthermore, the data confirm the presence of increased HGF/SF levels in human breast cancer when compared to tumour-free breast tissue. HGF/SF levels demonstrated statistically significant associations with disease-relapse and death. These findings concord with three similar studies 331,332,335.C-met protein was observed in all samples of tumour-free breast tissue and in a proportion of patients with breast cancer. Patients with detectable c-met demonstrated a significant association with disease relapse. This pattern of receptor expression and relationship to disease progression has subsequently been confirmed86. These observations provide strong support to the hypothesis that aberrant HGF/SF-c-met expression occurs in breast cancer. HGF/SF. angiogenesis and tumour cell proliferation in primary breast cancer In this study, a significant correlation between HGF/SF levels and tumour angiogenesis was observed in patients with breast cancer. Further evidence of a link between HGF/SF and tumour angiogenesis is provided by the observation of a direct relationship between HGF/SF and the endothelial cell marker, von Willebrand's factor, in breast cancer335. Also in this study, HGF/SF levels significantly correlated with KI-67 index and therefore tumour proliferation. HGF/SF is known to promote breast epithelial cell growth in vitro 115,208,252. However, HGF/SF promotion of breast cancer in vivo appears to be related to angiogenesis rather than direct stimulation of cellular proliferation 147. Conclusions The results of this thesis support the hypothesis that aberrant HGF/SF-c-met expression occurs in human breast cancer and is related to disease progression. HGF/SF expression in breast cancer is related to both angiogenesis and tumour proliferation. The involvement of a tumour suppressor gene at the c-met locus is not confirmed.