A Modulator of FGFs in Breast Cancer
GEORGETOWN UNIV WASHINGTON DC
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The growth of new blood vessels, or angiogenesis, is an important part of breast cancer biology. Our laboratory has found that a secreted binding protein for fibroblast growth factors FGF-BP is expressed in two breast cancer cell lines and primary breast tumor samples. In addition, FGF-BP is expressed in squamous cell carcinoma SCC and colon cancer and modulation of FGF-BP expression in these tumor types results in a significant effect on tumor growth and angiogenesis. To obtain a befter understanding of the regulation of FGF-BP and how its aberrant expression might lead to activation of angiogenic pathways, we have isolated the human FGF-BP promoter and have determined which functional promoter elements were necessary for its expression. In particular, we have found that the FGF-BP gene is transcriptionally up-regulated by the phorbol ester TPA, and by the epidermal growth factor EGF, both activating the protein kinase C PKC pathway in the MEl 80 SCC cell line. In the MEl 80 model, TPA-induced FGF-BP transcription is mediated through a juxtaposed SplAP-l positive regulatory element, as well as a CEBP element, in contrast to EGF- induced transcription only being mediated through the AP-l and CEBP regulatory elements. Furthermore, the presence of a distinct repressor element was detected whose normal function limits of the response of the promoter to TPA and EGF. Finally, we found that EGF, but not TPA, is able to up-regulate FGF-BP transcription in the MDA-MB-468 breast cancer cell line, mediated through the A- 1 and CEBP regulatory elements.
- Medicine and Medical Research