Two important factors which contribute to treatment failure for breast cancer are the metastatic potential of the tumor and the development of hormone independence. Experiments are proposed to elucidate the genetic mechanisms that underlie the progression of breast cancer from a poorly invasive hormone-dependent state to one that has an increased metastatic potential and is resistant to hormonal therapies. We have found that both of these phenotypes can be conferred to MCF-7 cells, a human breast cancer cell line that is hormone-dependent and noninvasive, by transfection and subsequent overexpression of FGF-4, a member of the heparin-binding fibroblast growth factor family. We have also found evidence for the widespread expression of FGF-1 and FGF receptors in human breast tumors. FGFs are angiogenic growth factors and overexpression of FGFs can confer a transformed phenotype. In other systems we have shown that both the autocrine and paracrine stimulatory effects of FGF expression on tumor growth can be abrogated by treatment with heparin-like compounds. This emphasized the potential clinical importance of an understanding of the role of FGF expression both in breast cancer progression and as a determinant in the efficacy of hormonal therapies. It also pointed out the utility of development in vivo and in vitro breast cancer model systems for the testing of antiangiogenic and antimetastatic agents for use in situations where conventional therapies alone would be unlikely to be effective. MCF-7 cells will be transfected with expression vectors for secreted and non-secreted forms of FGF-1 and with a FGF-1 cDNA deleted of a nuclear localization signal. This will allow us to determine if overexpression of a factor found in a large percentage of breast tumors can confer an estrogen-independent and metastatic phenotype and the role of growth factor secretion and nuclear localization in the process. The range of expression of FGF ligands and receptors in breast cancer tumors will be determined to identify potential prognostic indicators. An immunohistochemical assay for FGF-1 will be further developed. This assay will be used to determine the relationship of FGF-1 expression to the success of hormonal therapy and malignant progression. The utility of the FGF-4 transfected MCF-7 cells as an in vivo model for testing the antimetastatic effects of antiangiogenic agents AGM-1470 and pentosan polysulfate will be improved by further engineering with beta-galactosidase and collagenase IV expression vectors. This will result in cell lines with increased ease of detection at distant metastatic sites and the potential for increased metastasis due to the overexpression of an enzyme important in basement membrane degradation.
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