Sapi E, Flick M B, Gilmore-Hebert M, Rodov S, Kacinski B M
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06510-8040.
Oncogene. 1995 Feb 2;10(3):529-42.
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.
巨噬细胞集落刺激因子CSF-1及其受体（原癌基因c-fms）已在巨噬细胞、滋养层细胞以及包括乳腺癌在内的多种上皮源性肿瘤中被观察到。我们之前报道过（《癌基因》，1991年，6: 941 - 952），糖皮质激素可使几种乳腺癌细胞系中的c-fms转录本和蛋白表达显著增加，而糖皮质激素是正常乳腺上皮细胞分化所必需的体液调节因子。在本通讯中，我们证明在糖皮质激素处理的最初几个小时内，c-fms转录本和蛋白水平显著升高，并且用米非司酮（RU486）预处理细胞可完全消除这些升高。我们还证明c-fms转录本水平的这种早期升高不能归因于转录本半衰期的延长。发现c-fms基因的两个启动子在乳腺癌细胞系中均表现出一定的基础活性，并且两者均被糖皮质激素刺激2 - 3倍。然而，第一个启动子被证明负责超过95%的所观察到的c-fms转录。发现两个启动子上游的序列均含有潜在的“糖皮质激素反应元件”（GREs），并且在每种情况下，消除最靠近启动子的GRE可消除糖皮质激素刺激。我们的观察结果表明，糖皮质激素调节肿瘤性乳腺上皮细胞增殖和分化的一种机制是通过它们对一种普遍存在的细胞因子CSF-1受体基因转录的调节。
