Paradoxical hormone responses of KPL-1 breast cancer cells in vivo: A significant role of angiogenesis in tumor growth

In our previous study, the growth of KPL-1 human breast cancer cells was fo und 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 mec hanisms of these paradoxical responses, the effects of E2, ovariectomy (Ove x) and medroxyprogesterone acetate (MPA) on the growth, angiogenesis, apopt osis and expression of vascular endothelial growth factor (VEGF) were inves tigated. E2 stimulated the growth of KPL-1 cells but MPA inhibited it in vi tro. In contrast, E2 propionate inhibited the growth of KPL-1 cells in fema le nude mice but Over and MPA stimulated it. E2 propionate suppressed angio genesis and increased apoptosis in KPL-1 tumors, but Over 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 cell s they were both inhibited by MPA. E2 did not significantly influence VEGF expression in either cell line. These findings suggest that the abnormal mo dulation 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 viv o. To support this hypothesis, an antiangiogenic agent, TNP-470, was admini stered to mice bearing KPL-1 tumors. TNP-470 significantly inhibited the gr owth of KPL-1 tumors stimulated by MPA. Antiangiogenic agents may be effect ive for the treatment of hormone-refractory breast cancer. Copyright (C) 20 00 S. Karger AG, Basel.