Signal Transduction in Regulation of Autocrin HGF Expression in Breast Cancer Metastasis

Increased expression of hepatocyte growth factor HGF and its receptor Met has been identified as a possible independent indicator of recurrence in breast cancer patients. Dr. Elliotts laboratory has previously shown increased expression of EGE and Met in regions of invasive human breast cancer. In addition, we have found that breast carcinoma cell lines frequently express EGE and Met, whereas most nonmalignant epithelial cell lines express Met but not HGF. Together these results suggest that establishment of an autocrine EGE loop in carcinoma cells, and the change in the regulation of HGF expression is an important indicator of breast cancer progression. I have shown that in one breast carcinoma cell line MCFlOAl T3B expressed additional forms of HGF. This may represent one mechanism by which breast cancer cells regulate the pericellular level of HGF. I have identified 2 Stat3 binding sites on the HGF promoter, which are required for responsiveness of HGF transcription to the level of c-Src kinase activity. Changes in c-Src kinase activity affect Stat3 activity through its tyrosine phosphorylation and DNA binding affinity. Ras activity can also regulate HGF transcription in breast carcinoma cells, and preliminary evidence suggested phosphatidylinositol 3-kinase is a downstream target of this pathway.