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Submitted on June 23, 2004
Accepted on October 24, 2004
Dalton Cardiovascular Research Center and the Department of Biomedical Sciences, University of Missouri, Columbia, MO 65211
* To whom correspondence should be addressed. E-mail: hyders{at}missouri.edu.
We evaluated the signaling pathways involved in regulating vascular endothelial growth factor (VEGF), a potent angiogenic growth factor, in response to natural and synthetic progestins in breast cancer cells. Inhibition of the PI3-kinase signaling pathway or the SP-1 transcription factor abolished both progesterone- and medroxyprogesterone acetate (MPA)-induced VEGF secretion from BT-474 and T47-DCO cells. Inhibitors of the MEK1/2/MAPK and JNK/MAPK signaling pathways blocked both progesterone- and MPA-induced VEGF secretion in BT-474 cells. However, these inhibitors blocked only progesterone-, but not MPA-induced VEGF expression and secretion in T47-DCO cells. Inhibitors of PI3-kinase or SP-1 blocked both progesterone- and MPA-induced increases in VEGF mRNA levels in T47-DCO cells. The proximal SP-1 sites within the VEGF promoter were critical for progestin-dependent induction of VEGF. In contrast, MAPK inhibitors did not block the progesterone- or MPA-induced increases in VEGF mRNA in T47-DCO cells, suggesting that MAPK inhibitors decreased progesterone-induced VEGF secretion in T47-DCO cells by blocking post-transcriptional mechanisms. The MEK/ERK/MAPK-independent induction of VEGF mediated by MPA was associated with the PRB isoform of the progesterone receptor (PR) in T47-DCO cells. None of the inhibitors tested reduced basal PR levels or abrogated PR-dependent gene expression from a reporter plasmid, indicating that loss of PR function cannot explain any of the observed effects. Since the PI3-kinase signaling pathway and SP-1 transcription factor play critical roles in progestin-dependent VEGF induction, these may be useful targets for developing anti-angiogenic therapies to prevent progression of progestin-dependent human breast cancers.
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