Signal Transduction in Regulation of Autocrin HGF Expression in Breast Cancer Metastasis
Abstract
In the normal breast, hepatocyte growth factor (HGF), also known as scatter factor, is expressed primarily by stromal cells, while epithelial cells express the HGF receptor, Met. Thus, epithelial cells exhibit a tight paracrine loop regulating HGF-dependent responsiveness. In invasive human breast carcinomas, HGF and Met are frequently over-expressed, thereby establishing an autocrine HCF/Met signaling pathway and promoting tumor cell invasion. However, the mechanisms leading to aberrant expression of HGF in carcinoma cells are not known. We previously demonstrated a co-operative effect of c-Src tyrosine kinase and Stat3 in the activation of HGF transcription in mammary carcinoma cells. In the present report, we have shown that non-malignant breast epithelial cells over-expression activated c-Src and Stat3 exhibit increased activation of Stat3, HGF transcription, and cell scattering. Mutational analysis of the HGF promoter revealed a novel Stat3 binding site at nt -95, which is required for the c-Src/Stat3 co-operative effect. Our results delineate a novel c-Src/Stat3-dependent mechanism that regulates HGF transcription in breast carcinomas. This study could lead to novel strategies inhibition of HGF gene expression in tumor cells with minimal effects on normal HGF/Met function.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2003
- Accession Number
- ADA420962
Entities
People
- Joanna Wojcik
Organizations
- Queen's University