Both Autocrine and Paracrine Effects of Transfected Acidic Fibroblast Growth Factor Are Involved in the Estrogen-independent and Antiestrogen-resistant Growth of MCF-7 Breast Cancer Cells

To determine the extent to which autocrine effects of acidic fibroblast growth factor (FGF)-1 overexpression contribute to an increased malignant phenotype, FGF-1-transfected MCF-7 cells were retransfected with a FGF receptor (FGFR1) vector encoding a truncated dominant-negative receptor to inhibit autocrine FGF signal transduction. This transfection eliminated FGF signaling within the breast cancer cells without interfering with their ability to produce FGF-1, thereby allowing possible paracrine effects to still be observed in vivo . Truncated FGFR1 overexpression inhibited the acquired ability of FGF-1-overexpressing cells to form colonies in soft agar in estrogen-depleted or antiestrogen-containing medium. However, soft agar colony formation was still stimulated by estrogen treatment in cells expressing up to 6 × 105 truncated FGFR1 sites per cell. In vivo , truncated receptor expression severely inhibited the ability of the FGF-1-overexpressing cells to form tumors without estrogen in ovariectomized mice, indicating that the mitogenic effect of FGF-1 on the breast tumor cells was important in the estrogen-independent in vivo growth of these transfectants. However, rapid formation of large tumors was still observed in estrogen-supplemented mice injected with the truncated FGFR1-expressing cells, suggesting that the paracrine effects of FGF production could act in synergy with mitogenic effects mediated by estrogen. Truncated FGFR1-overexpressing cells also continued to form tumors in tamoxifen-treated mice, raising the possibility that the paracrine effects of FGF-1 expression may allow the partial agonist properties of this antiestrogen to be more readily observed. We conclude that autocrine effects of FGF-1 increase the ability of MCF-7 breast cancer cells to grow in vitro and in vivo under estrogen-depleted conditions but that paracrine effects of FGF-1 are also involved in the enhancement of tumor growth in estrogen-supplemented or tamoxifen-treated animals.