TRANSCRIPTIONAL REGULATION OF THE C-FMS (CSF-1R) PROTOONCOGENE IN HUMAN BREAST-CARCINOMA CELLS BY GLUCOCORTICOIDS

Expression of the macrophage colony stimulating factor CSF-1 and its r eceptor, the c-fms proto-oncogene, has been observed in macrophages, t rophoblast and in a variety of neoplasms of epithelial origin includin g those of the breast. We have reported earlier (Oncogene, 1991, 6: 94 1-952) that c-fms transcript and protein expression were dramatically increased in several breast carcinoma cell lines by glucocorticoids wh ich are essential humoral regulators of normal mammary epithelial cell differentiation. In this communication, we demonstrate that levels of c-fms transcript and protein increased significantly within the first few hours of glucocorticoid treatment, and that these increases were completely abolished by pretreatment of cells with mifepristone (RU486 ). We also demonstrate that such early increases in c-fms transcript l evels could not be attributed to prolongation of transcript half-life. Both promoters of the c-fms gene were found to exhibit some basal act ivity in breast carcinoma cell lines and both were stimulated 2-3-fold by glucocorticoids. However the first promoter was shown to be respon sible for more than 95% of the observed c-fms transcription. Sequence upstream of both promoters was found to contain potential 'glucocortic oid response elements' (GREs), and in each case, elimination of the GR E closest to the promoter abolished glucocorticoid stimulation. Our ob servations suggest that one mechanism by which glucocorticoids regulat e the proliferation and differentiation of neoplastic mammary epitheli al cells is through their regulation of transcription of the gene for the receptor of a ubiquitous cytokine, CSF-1.