The long term goal of this project is to understand the immune mechanisms that control breast cancer invasiveness (malignancy). One of the earliest changes triggered by malignant transformation is the dramatic formation of cell surface protrusions, invadopodia, and shed membrane vesicles that express active extracellular matrix-degrading, plasma membrane-associated proteases including collagenases. Preliminary data indicate that, in established cell lines with differential invasiveness, these membrane proteases are down-regulated in differentiated cells, up- regulated in benign hormone-dependent breast carcinoma, and over- expressed on the cell surface of invasive hormone-independent breast carcinoma. Basic information on these newly discovered molecules is not available.
The aims of this application will focus on the molecular identification of breast cancer membrane proteases.
Four specific aims are: (1) to perform the molecular identification of membrane proteases including characterization of their polypeptides and genes, (2) to determine the functional role of membrane proteases in interacting with collagenases during localized basement membrane degradation and in experimental animals or breast cancer patients, and (3) to evaluate membrane proteases as relevant breast cancer antigens by (a) examining possible immune responses in experimental animals or breast cancer patients including T lymphocyte activation, and (b) determining its gene expression during malignant transformation in the in vitro and in vivo models of breast cancers.
These aims test the hypothesis that malignant transformation of breast cells leads to specific expression of membrane proteases on the cell surface, that may regulate the invasion of epithelial cells through their underlying basement membrane and stroma leading to important changes in stromal-epithelial interactions as well as in immune responses. The results of this study can lead to the development of effective strategies for immunologically-based prevention or treatment of breast cancer.
| Chen, W T (1996) Proteases associated with invadopodia, and their role in degradation of extracellular matrix. Enzyme Protein 49:59-71 |
| Chen, W T; Lee, C C; Goldstein, L et al. (1994) Membrane proteases as potential diagnostic and therapeutic targets for breast malignancy. Breast Cancer Res Treat 31:217-26 |
