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Complex Regulation of the Fibroblast Growth Factor-binding Protein in MDA- MB-468 Breast Cancer Cells by CCAAT/Enhancer-binding Protein ß¹

Departments of Pharmacology [B. L. K., A. W., A. T. R.] and Oncology [R. T. H., R. C-M., G. E. S., Q. N., A. W., A. T. R.], Vincent T. Lombardi Cancer Center, Georgetown University, Washington, DC 20057

The fibroblast growth factor-binding protein (FGF-BP) binds and activates fibroblast growth factors in the extracellular matrix, and can have a rate-limiting role in tumor angiogenesis. Here we demonstrate high levels of FGF-BP expression in invasive human breast cancer, relative to normal breast and in situ carcinoma, and in MDA-MB-468 human breast cancer cells. In these cells, FGF-BP was up-regulated by treatment with epidermal growth factor (EGF), dependent on protein kinase C and p38 mitogen-activated protein kinase signaling. Mutational analysis revealed that the activator protein 1 and CCAAT/enhancer binding protein (C/EBP) sites on the FGF-BP gene promoter were required for the EGF effect, whereas deletion of the C/EBP site resulted in a significant increase in promoter basal activity indicating a basal repressive control mechanism. These data suggest that the C/EBP site is a central regulatory element for the regulation of FGF-BP promoter activity in MDA-MB-468 cells. We found that MDA-MB-468 cells express high endogenous levels of both the activating (LAP) and repressive (LIP) isoforms of C/EBPß. Overexpression of C/EBPß-LAP in MDA-MB-468 cells resulted in a large 80-fold increase in FGF-BP promoter basal activity, which was reversed by coexpression of LIP. Gel-shift analysis revealed that four LIP- and LAP-containing complexes (a-d) bind to the C/EBP site. DNA binding of the LIP and LAP-containing c complex and the b complex in the presence of EGF was modulated by inhibition of p38 mitogen-activated protein kinase, suggesting a role for these complexes in the EGF induction of the FGF-BP promoter. This study suggests that along with its well-defined role in mammary gland development, C/EBPß may well play a role in the pathology of breast cancer, in particular in the control of angiogenesis in the invasive phenotype.

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