Signal Transduction in Regulation of Autocrin HGF Expression in Breast Cancer Metastasis
Abstract
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. Elliott's laboratory has previously shown increased expression of HGF and Met in regions of invasive human breast cancer. In addition, we have found that breast carcinoma cell lines frequently express HGF and Met, whereas most nonmalignant epithelial cell lines express Met but not HGF. Together, these results suggest that establishment of an autocrine HGF loop in carcinoma cells, and the change in transcriptional and post- transcriptional control of HGF expression is an important indicator of breast cancer progression. Therefore the objectives of my project are a) to examine the transcriptional and post-transcriptional control of HGF expression, and b) to determine the role of signaling molecules in HGF expression in breast carcinoma cells. I have shown that HGF is expressed in many breast carcinoma cell lines and in one particular cell line MCF10A1T3B additional forms of HGF are found. These additional HGF forms are likely the results of proteolytic activity and may represent one mechanism by which the breast carcinoma cells regulate the pericellular level of mature HGF. In addition, I have identified 2 regions in the HGF promoter that are responsive to increased c-Src kinase activity. I have shown previously that c-Src kinase is activated in a mouse breast carcinoma cell line, SP 1, and c-Src kinase activity is required for HGF-induced motility and anchorage-independent growth of these cells. Expression of an activated form of c-Src (Y327F) increases transcription from the HGF promoter and co-expression of Stat3 transcription factor synergistically increases HGFpromoter activity. These results suggest that c-Src tyrosine kinase activity regulates HGF expression and may be important in the establishment of an HGF autocrine loop in breast carcinoma cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 1999
- Accession Number
- ADA382801
Entities
People
- Peter Greer
- Wesley L. Hung
Organizations
- Queen's University