Transcriptional regulation of the c-fms (CSF-1R) proto-oncogene in human breast carcinoma cells by glucocorticoids.
Expression of the macrophage colony stimulating factor CSF-1 and its receptor, the c-fms proto-oncogene, has been observed in macrophages, trophoblast and in a variety of neoplasms of epithelial origin including those of the breast. We have reported earlier (Oncogene, 1991, 6: 941-952) that c-fms transcript and protein expression were dramatically increased in several breast carcinoma cell lines by glucocorticoids which 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 levels could not be attributed to prolongation of transcript half-life. Both promoters of the c-fms gene were found to exhibit some basal activity in breast carcinoma cell lines and both were stimulated 2-3-fold by glucocorticoids. However the first promoter was shown to be responsible for more than 95% of the observed c-fms transcription. Sequence upstream of both promoters was found to contain potential 'glucocorticoid response elements' (GREs), and in each case, elimination of the GRE closest to the promoter abolished glucocorticoid stimulation. Our observations suggest that one mechanism by which glucocorticoids regulate the proliferation and differentiation of neoplastic mammary epithelial cells is through their regulation of transcription of the gene for the receptor of a ubiquitous cytokine, CSF-1.
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06510-8040.
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Sapi
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Flick
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Gilmore-Hebert
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Rodov
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Kacinski
D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D003907:Dexamethasone / Q000494:pharmacology; D005091:Exons; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D016236:Genes, fms; D005938:Glucocorticoids / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000502:physiology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000502:physiology
D005938:Glucocorticoids; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D003907:Dexamethasone; D016186:Receptor, Macrophage Colony-Stimulating Factor