The role of hepatocyte growth factor (scatter factor) in epithelial-mesenchymal transition and breast cancer.
North American women have a one in eight lifetime risk of developing breast cancer, and approximately one in three women with breast cancer will die of metastases. We, and others, have recently shown that high levels of expression of hepatocyte growth factor (HGF) and its receptor Met are associated with invasive human breast cancer and may be causally linked to metastasis. This high level of HGF and Met expression has been considered as a possible indicator of earlier recurrence and shortened survival in breast cancer patients. In contrast, HGF expression (but not Met) is strongly suppressed in normal breast epithelial cells. HGF and Met are therefore candidate targets for therapeutic intervention in the treatment of breast cancer. We have recently demonstrated that sustained activation or hyper-activation of c-Src and Stat3, which occurs in invasive breast cancer, can stimulate strong expression of HGF in carcinoma cells. In contrast, transient induction of Stat3 occurs in normal epithelium and promotes mammary tubulogenesis. We hypothesize that increased autocrine HGF-Met signaling is a critical downstream function of c-Src-Stat3 activation in mammary tumorigenesis. Future studies will identify novel Stat3 consensus sites that regulate HGF promoter activity and HGF expression preferentially in carcinoma cells and could lead to novel therapeutic drugs that specifically block HGF expression in mammary carcinoma cells, and which could be used in combined treatments to abrogate metastasis.
Elliott
Bruce E
BE
Cancer Research Laboratories, Department of Pathology, Queen's University, Kingston, Canada. elliottb@post.queensu.ca
Hung
Wesley L
WL
Boag
Alexander H
AH
Tuck
Alan B
AB
D001940:Breast / Q000503:physiopathology; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D000081247:CSK Tyrosine-Protein Kinase; D015820:Cadherins / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D018450:Disease Progression; D004848:Epithelium / Q000473:pathology; D005109:Extracellular Matrix / Q000235:genetics / Q000502:physiology; D005260:Female; D015870:Gene Expression; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008648:Mesoderm / Q000473:pathology*; D009362:Neoplasm Metastasis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology; D019061:src-Family Kinases
D015820:Cadherins; D004268:DNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D017228:Hepatocyte Growth Factor; D011505:Protein-Tyrosine Kinases; D019859:Proto-Oncogene Proteins c-met; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human