The anticancer agent YC-1 suppresses progestin-stimulated VEGF in breast cancer cells and arrests breast tumor development

Carroll,Candace  E.; Liang,Yayun; Benakanakere,Indira; Besch-Williford,Cynthia; Hyder,Salman  M.

doi:10.3892/ijo.2012.1675

The anticancer agent YC-1 suppresses progestin-stimulated VEGF in breast cancer cells and arrests breast tumor development

Authors:
- Candace E. Carroll
- Yayun Liang
- Indira Benakanakere
- Cynthia Besch-Williford
- Salman M. Hyder
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Affiliations: Department of Biomedical Sciences and Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA, IDEXX RADIL, Columbia, MO 65201, USA
Published online on: October 24, 2012 https://doi.org/10.3892/ijo.2012.1675
Pages: 179-187

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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.

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