The c-Kit protooncogene is vital to survival. It is expressed in several normal tissues and in some neoplastic diseases. It and its ligand act as a survival factor or as a proliferation-differentiation factor for certain cells. The broad objective is to test the general hypothesis that c-Kit receptor expression is inversely correlated with clinical outcome in women with breast carcinoma. Initially, this will be tested by determining the prognostic importance of this receptor in subsets of women with this disease and by determining part of the biological significance of its expression.
The Specific Aims are: 1. Ascertain if the level of surface c-Kit is inversely correlated with specific aspects of breast carcinogenesis. To begin to define the role of c-Kit in breast cancer, its expression will be tested as a prognostic marker for (a) high risk of recurrence and therefore micrometastasis; (b) response to high dose chemotherapy and therefore a potential marker for response to autologous transplantation therapy. Two databases will be used. The first is a tissue/data bank, spanning a fifteen year period, consisting of all patients, over 750, treated in a uniform manner. The second is a tissue/data bank from a previous SWOG study which looked at different doses and intensity of chemotherapy. The tissue will be analyzed for c-Kit, and HER-2, by antibody/alkaline phosphatase staining and levels quantitated by two investigators. Correlations with expression will be analyzed by multivariate statistical techniques. 2. Develop an animal model of metastatic breast cancer to evaluate the biological effect of c-Kit. This will test the hypothesis that c-Kit expression is inversely related to the metastatic potential of a breast cancer cell. The commonly used, c-Kit negative cell line, 435, which is rapidly metastatic in nude mice, will be used. It will be transfected without or with control vectors or vectors expressing c-Kit at either moderate or high levels. Nude mice will be injected and the effect on the number and size of metastatic lesions determined. These preliminary biological studies will be correlated with the clinical studies of Specific Aim 1. These results could lead to specific subgroup therapy and to more directly exploiting the findings in a clinical manner.
