title: The anticancer agent YC-1 suppresses progestin-stimulated VEGF in breast             cancer cells and arrests breast tumor development.
abstract: Recent epidemiological studies show that postmenopausal women taking estrogen-progestin hormone replacement therapy (HRT) have a higher risk of breast cancer than women on an HRT regimen lacking progestins. This may be related to the observation that progestin-treated breast cancer cells express and secrete high levels of vascular endothelial growth factor (VEGF), a potent angiogenic factor that promotes breast tumor growth. Anti-progestins such as RU-486 block this effect, indicating that progesterone receptors (PR) are involved in promoting VEGF induction; however antiprogestins cross-react with other steroid receptors which limits their clinical use. Alternative strategies are, therefore, needed to arrest the growth of progestin-dependent tumors. 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), a novel anticancer drug initially developed as an inhibitor of HIF-1α, is currently undergoing preclinical trials against various forms of cancer. Since HIF-1α has recently been implicated in PR-mediated VEGF synthesis, we undertook studies to determine whether YC-1 inhibits progestin-dependent VEGF induction and tumor progression. Surprisingly, we found that YC-1 downregulated PR in human breast cancer cells, both in vivo and in vitro, thereby blocking progestin-dependent induction of VEGF and tumor growth. YC-1 also inhibited progestin-accelerated DMBA-induced mammary tumors in rats, properties which would likely render it effective against progestin-dependent tumors which frequently develop in post-menopausal women. We, therefore, propose that based on our observations, YC-1 warrants further investigation as a novel agent which could prove extremely useful as an anti-angiogenic chemotherapeutic drug.
authors.affiliation: Department of Biomedical Sciences, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Candace E
authors.initials: CE
authors.lastname: Carroll
authors.forename: Yayun
authors.initials: Y
authors.lastname: Liang
authors.forename: Indira
authors.initials: I
authors.lastname: Benakanakere
authors.forename: Cynthia
authors.initials: C
authors.lastname: Besch-Williford
authors.forename: Salman M
authors.initials: SM
authors.lastname: Hyder
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D020536:Enzyme Activators / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006162:Guanylate Cyclase / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D007124:Immunoenzyme Techniques; D007191:Indazoles / Q000494:pharmacology*; D015674:Mammary Neoplasms, Animal / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008819:Mice, Nude; D015735:Mifepristone / Q000494:pharmacology; D010880:Piperidines / Q000633:toxicity; D011372:Progestins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C556780:3-(2,6-bis(4-fluorophenyl)-3-methylpiperidin-4-ylideneamino)-2-thioxoimidazolidin-4-one on 7,12-dimethylbenz(a)anthracene; D000873:Anthracenes; D020536:Enzyme Activators; D006727:Hormone Antagonists; D007191:Indazoles; D010880:Piperidines; D011372:Progestins; D012333:RNA, Messenger; D011980:Receptors, Progesterone; D042461:Vascular Endothelial Growth Factor A; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D015735:Mifepristone; D006162:Guanylate Cyclase