In our previous study, the growth of KPL-1 human
breast cancer cells was found to be stimulated by an
antiestrogen, ICI 182, 780, and inhibited by
17 beta-estradiol (E2) in vivo but not in vitro. To investigate the action mechanisms of these paradoxical responses, the effects of E2,
ovariectomy (
Ovex) and
medroxyprogesterone acetate (MPA) on the growth, angiogenesis, apoptosis and expression of
vascular endothelial growth factor (
VEGF) were investigated. E2 stimulated the growth of KPL-1 cells but MPA inhibited it in vitro. In contrast, E2
propionate inhibited the growth of KPL-1 cells in female nude mice but
Ovex and MPA stimulated it. E2
propionate suppressed angiogenesis and increased apoptosis in KPL-1
tumors, but
Ovex and MPA promoted angiogenesis and decreased apoptosis. Both
mRNA expression and secretion of
VEGF were stimulated by MPA in KPL-1 cells, but in E2-dependent ML-20 cells they were both inhibited by MPA. E2 did not significantly influence
VEGF expression in either cell line. These findings suggest that the abnormal modulation of
VEGF expression by MPA and of the other
angiogenic factor by E2 are responsible for the paradoxical growth responses of KPL-1 cells in vivo. To support this hypothesis, an
antiangiogenic agent,
TNP-470, was administered to mice bearing KPL-1
tumors.
TNP-470 significantly inhibited the growth of KPL-1
tumors stimulated by MPA.
Antiangiogenic agents may be effective for the treatment of
hormone-refractory
breast cancer.