COEXPRESSION OF THE C-KIT AND STEM-CELL FACTOR GENES IN BREAST CARCINOMAS

Expression of the c-kit tyrosine kinase growth factor receptor has bee n reported in some breast tumors; however, no data exist concerning ex pression of its ligand, stem cell factor. The aim of this study was to determine how frequently the c-kif and stem cell factor genes were co expressed in breast tumors and tumor-derived cell lines and to determi ne whether coexpression of c-kif and stem cell factor could result in growth stimulation of breast tumor cells. Expression of the c-kif and stem cell factor genes in tissue specimens and cell lines was determin ed using an RNase protection assay, with confirmation of c-kit protein expression by immunohistochemistry and Western blotting in tumor tiss ue and cell lines, respectively. Of 11 tumor specimens studied, 9 expr essed variable but detectable quantities of c-kif; 7 of 13 tumor-deriv ed cell lines also expressed c-kif. All tumor specimens and cell lines expressed detectable stem cell factor mRNA, suggesting that an autocr ine growth loop could exist in the majority of breast carcinomas. To d etermine the biological effects of coexpression of c-kif and stem cell factor, the MCF-7 cell line, which expresses only stem cell factor, w as transfected with a c-kif expression vector. Coexpression of c-kit a nd stem cell factor in MCF-7 cells resulted in an enhanced growth rate and cloning efficiency but not a loss of the dependence of this cell line upon estrogen. Analysis of subclones expressing different amounts of c-kit protein revealed that, although they all showed enhanced gro wth relative to control transfectants in serum-free medium containing IGF-1, only the highest c-kit expressor responded with additional grow th to exogenous soluble stem cell factor. However, all c-kit-expressin g clones, but not control clones, showed growth inhibition when expose d to a blocking anti-c-kif antibody. This blocking antibody also signi ficantly inhibited the growth of the established ZR75-1 cell line in s erum-free medium containing IGF-1. Taken together, these data suggest that coexpression of stem cell factor and c-kif could be responsible f or growth deregulation in a significant number of breast carcinomas.