Progestin-dependent progression of human breast tumor xenografts: a novel model for evaluating antitumor therapeutics.
Recent clinical trials indicate that synthetic progestins may stimulate progression of breast cancer in postmenopausal women, a result that is consistent with studies in chemically-induced breast cancer models in rodents. However, progestin-dependent progression of breast cancer tumor xenografts has not been shown. This study shows that xenografts obtained from BT-474 and T47-D human breast cancer cells without Matrigel in estrogen-supplemented nude mice begin to regress within days after tumor cell inoculation. However, their growth is resumed if animals are supplemented with progesterone. The antiprogestin RU-486 blocks progestin stimulation of growth, indicating involvement of progesterone receptors. Exposure of xenografts to medroxyprogesterone acetate, a synthetic progestin used in postmenopausal hormone replacement therapy and oral contraception, also stimulates growth of regressing xenograft tumors. Tumor progression is dependent on expression of vascular endothelial growth factor (VEGF); growth of progestin-dependent tumors is blocked by inhibiting synthesis of VEGF or VEGF activity using a monoclonal anti-VEGF antibody (2C3) or by treatment with PRIMA-1, a small-molecule compound that reactivates mutant p53 into a functional protein and blocks VEGF production. These results suggest a possible model system for screening potential therapeutic agents for their ability to prevent or inhibit progestin-dependent human breast tumors. Such a model could potentially be used to screen for safer antiprogestins, antiangiogenic agents, or for compounds that reactivate mutant p53 and prevent progestin-dependent progression of breast disease.
Liang
Yayun
Y
Dalton Cardiovascular Research Center, Veterinary Pathobiology, and Department of Biomedical Sciences, University of Missouri, Columbia, Missouri 65211, USA.
Besch-Williford
Cynthia
C
Brekken
Rolf A
RA
Hyder
Salman M
SM
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D001372:Aza Compounds / Q000494:pharmacology; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D048708:Cell Growth Processes / Q000187:drug effects; D018450:Disease Progression; D005260:Female; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology; D009376:Neoplasms, Hormone-Dependent / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D011374:Progesterone / Q000494:pharmacology; D045167:Progesterone Congeners / Q000494:pharmacology; D011372:Progestins / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000096:biosynthesis; D011980:Receptors, Progesterone / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D001372:Aza Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D045167:Progesterone Congeners; D011372:Progestins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D042461:Vascular Endothelial Growth Factor A; D015735:Mifepristone; D011374:Progesterone; D017258:Medroxyprogesterone Acetate; D040301:Vascular Endothelial Growth Factor Receptor-2; C451219:2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one