Members of the
fibroblast growth factor (FGF) family have been associated with
tumor progression and angiogenesis, though the mechanism through which they affect the progression of
breast cancer remains elusive. We recently showed that
progestins increase the production of the potent
angiogenic factor VEGF in an in vivo BT-474 human
breast cancer cell-derived xenograft model. In this study we sought to determine the effect of
progesterone (P) on regulation of specific FGF family members (FGF-2, FGF-4 and FGF-8) in the same model. Using immunohistochemistry we found that treatment with P significantly reduced
FGF-2 and FGF-8 levels, while modestly increasing the levels of FGF-4 in
tumors collected at the termination of the study or soon after P treatment began. The in vivo observations with
FGF-2 were confirmed in cultured BT-474 cells, though the P-mediated reduction in
FGF-2 was not blocked by the anti-
progestin RU-486, suggesting that classical
progesterone receptors (PR) are not involved in
FGF-2 down-regulation. Also, P did not affect levels of
FGF-2 mRNA in BT-474 cells, indicating that P exerts its effects on
FGF-2 post-transcriptionally. Our observations suggest that the in vivo stimulation of BT-474 cell growth by P is associated with down-regulation of
FGF-2 and FGF-8. Furthermore, since FGF-4 levels increased during P-treatment, FGF-4 may be required for
tumor growth and maintenance and might therefore be a potential therapeutic target through which to suppress P-dependent
tumor growth.