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 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.
Kurebayashi
J
J
Department of Breast and Thyroid Surgery, Kawasaki Medical School, Kurashiki, Okayama, Japan. kure@med.kawsaki-m.ac.jp
Kunisue
H
H
Yamamoto
S
S
Kurosumi
M
M
Otsuki
T
T
Sonoo
H
H
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D003510:Cyclohexanes; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D008940:Mitotic Index / Q000187:drug effects; D009389:Neovascularization, Pathologic; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000903:Antibiotics, Antineoplastic; D018931:Antineoplastic Agents, Hormonal; D003510:Cyclohexanes; D016228:Endothelial Growth Factors; D008222:Lymphokines; D012333:RNA, Messenger; D012717:Sesquiterpenes; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D017258:Medroxyprogesterone Acetate; D000077609:O-(Chloroacetylcarbamoyl)fumagillol