Tissue microarray analysis of hepatocyte growth factor/Met pathway components reveals a role for Met, matriptase, and hepatocyte growth factor activator inhibitor 1 in the progression of node-negative breast cancer.
Numerous studies have demonstrated that overexpression of Met, the hepatocyte growth factor(HGF) receptor, plays an important role in tumorigenesis. Met activation can either occur through ligand-independent or -dependent mechanisms, both of which are mediated by a series of proteases and modulators. We studied the protein expression of several components of the HGF/Met pathway on a cohort of 330 node-negative breast carcinomas using a tissue microarray annotated with 30-year, disease-specific patient follow-up data. We examined HGF, matriptase (an activator of HGF expressed on mammary epithelial cell surfaces), HAI-I (the cognate inhibitor of matriptase), and the Met receptor itself. Our studies demonstrate tight correlation between the expression of HGF, matriptase, and Met in breast carcinoma. High-level expression of Met, matriptase, and HAI-I were associated with poor patient outcome. Met and HAI-I showed independent prognostic value when compared with traditional breast markers in a multivariate analysis. Intriguingly, antibodies against the intracellular but not the extracellular domain of Met were prognostic, suggesting that overexpression of the cytoplasmic-tail of Met, perhaps through cleavage or truncating mutation, may play an important role in breast cancer progression.
Kang
Jung Y
JY
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Dolled-Filhart
Marisa
M
Ocal
Idris Tolgay
IT
Singh
Baljit
B
Lin
Chen-Yong
CY
Dickson
Robert B
RB
Rimm
David L
DL
Camp
Robert L
RL
D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis* / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D011379:Prognosis; D053491:Proteinase Inhibitory Proteins, Secretory; D011518:Proto-Oncogene Proteins; D019859:Proto-Oncogene Proteins c-met; D017978:Receptors, Growth Factor; D012697:Serine Endopeptidases / Q000096:biosynthesis*; D015534:Trans-Activators / Q000096:biosynthesis*; D014357:Trypsin / Q000096:biosynthesis*
D008562:Membrane Glycoproteins; D053491:Proteinase Inhibitory Proteins, Secretory; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; C109149:SPINT1 protein, human; D015534:Trans-Activators; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D012697:Serine Endopeptidases; C485595:matriptase; C485596:ST14 protein, human; D014357:Trypsin