Expression of the c-Met/HGF receptor in human breast carcinoma: correlation with tumor progression.
Hepatocyte growth factor/scatter factor (HGF/SF) induces cell motility and tissue remodeling of various epithelial cells through its receptor, the product of the proto-oncogene c-met. High levels of HGF/SF have been correlated with poor prognosis in human breast carcinoma. In this study, we examined the expression of the c-Met receptor in human breast-carcinoma cells in vivo and in cultured cell lines. Immunohistochemical analysis of biopsy samples of human breast carcinoma indicated that, in normal mammary gland, c-Met is localized in the ductal epithelium. The level of expression of c-Met in primary carcinomas was maintained in autologous metastatic lymph-node lesions in some cases, and in other cases was elevated. Frequently there was evidence of heterogeneity in cellular expression of c-Met within individual tumors, suggesting that micro-environmental factors may regulate receptor expression. In an analysis of a panel of human breast-carcinoma cell lines, we found that moderately differentiated cell lines did not express detectable levels of c-Met and were not responsive to HGF. In contrast, poorly differentiated and invasive cell lines did express high levels of the receptor and responded to HGF by increased motility and invasiveness. Sensitivity to HGF/SF also correlated with expression of the c-Met 9-kb mRNA. No correlation was found between gene copy number and the expression level of c-Met protein or mRNA. When the moderately differentiated and c-Met-negative T47D cell line was transfected with c-DNA for c-met, the transfectants showed delayed cell scattering and migratory response to HGF. Thus, over-expression of c-Met in moderately differentiated carcinoma cells may be one of several attributes that contribute to an invasive phenotype during the progression of breast cancer.
Beviglia
L
L
Department of Stomatology, and the Cardiovascular Research Institute, University of California, San Francisco 94143-0512, USA.
Matsumoto
K
K
Lin
C S
CS
Ziober
B L
BL
Kramer
R H
RH
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000187:drug effects; D018450:Disease Progression; D005260:Female; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009361:Neoplasm Invasiveness; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met; D012333:RNA, Messenger / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases