Hepatocyte Growth Factor/Scatter Factor and Its Receptor c-Met Modulate E-Cadherin Expression in Matrix-Producing Breast Carcinomas
K Gwin, A Acurio, R Buell-Gutbrod. University of Chicago, Chicago, IL
Background: Hepatocyte growth factor (HGF)/ scatter factor (SF) is a cytokine known to regulate epithelial mesenchymal transition (EMT) and to stimulate proliferation, motility, angiogenesis and invasion in various cell types, including breast carcinomas. Its biologic signal is transmitted via the HGF receptor c-Met. E-cadherin plays an important role in the maintenance of epithelial cell-cell adhesions. HGF phosphorylates β-catenin and modulates the E-cadherin complex mediated cell-cell adhesions by β-catenin dissociation from E-cadherin, leading to distribution of E-cadherin from a functional to a nonfunctional compartment in the cell. Matrix-producing breast carcinoma (MBC) show a mixed epithelial and mesenchymal chondromyxoid matrix with features reminiscent of EMT and therefore are a potential in vivo model for EMT. In this study we investigated the correlation of HGF/SF, c-Met and E-Cadherin expression in both tumor components.
Design: Archival paraffin embedded material of twelve matrix-producing breast carcinomas as defined by the 2003 WHO classification were examined by IHC for the expression and localization of HGF/SF, c-Met and E-cadherin.
Results: Overall, 92% of study cases revealed cytoplasmic HGF and c-Met expression. The HGF immunoreactivity was mainly located at the interface of cellular areas with chondroid elements and adjacent to conventional invasive ductal carcinoma. C-Met was equally expressed in both tumor components. For E-cadherin, 83% of cases showed membranous staining in the conventional ductal carcinoma, reduced expression at the interface, and complete loss of expression in the metaplastic component. Two cases were completely negative for E-cadherin.
Conclusions: The MBC included in this study showed a high frequency of c-Met receptor protein activation, which is the only known receptor for HGF/SF. Our study revealed an inverse correlation between HGF expression and membranous E-cadherin immunoreactivity, supporting HGF's role in modulation of E-cadherin. Of interest was the reduced E-cadherin expression in the chondroid metaplastic component. Loss of E-cadherin expression leads to less cell-cell adhesions and increased motility of cells (cell 'scattering'), both of which are features of epithelial-mesenchymal transition (EMT). Our findings therefore suggest that the tumor cells of the metaplastic chondroid component acquire a mesenchymal phenotype by undergoing EMT. This might contribute to the high metastatic potential and the known aggressive clinical behavior of MBC.
Wednesday, March 24, 2010 1:00 PM
Poster Session VI # 19, Wednesday Afternoon