Ligand- and cell-specific effects of signal transduction pathway inhibitors on progestin-induced vascular endothelial growth factor levels in human breast cancer cells.

Abstract

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 phosphoinositide-3'-kinase (PI3-kinase) signaling pathway or the specificity protein-1 (SP-1) transcription factor abolished both progesterone- and medroxyprogesterone acetate (MPA)-induced VEGF secretion from BT-474 and T47-DCO)cells. Inhibitors of the MAPK kinase 1/2/MAPK and N-terminal jun kinase/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 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 posttranscriptional mechanisms. The MAPK kinase/ERK/MAPK-independent induction of VEGF mediated by MPA was associated with the PRB [progesterone receptor (PR) B] isoform of the 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. Because 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 antiangiogenic therapies to prevent progression of progestin-dependent human breast cancers.

• Authors: Jianbo Wu, Sandra Brandt, Salman M Hyder
• Journal: Molecular endocrinology (Baltimore, Md.) (Mol Endocrinol) Vol. 19 Issue 2 Pg. 312-26 (Feb 2005) ISSN: 0888-8809 [Print] United States
• PMID: 15528272 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents, Hormonal
• Enzyme Inhibitors
• Ligands
• Progestins
• Protein Isoforms
• RNA, Messenger
• Vascular Endothelial Growth Factor A
• Progesterone
• Medroxyprogesterone Acetate
• Luciferases
• Phosphatidylinositol 3-Kinases

Topics

• Antineoplastic Agents, Hormonal (pharmacology)
• Base Sequence
• Breast Neoplasms (metabolism)
• Cell Line, Tumor
• Disease Progression
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Enzyme-Linked Immunosorbent Assay
• Humans
• Immunoblotting
• Ligands
• Luciferases (metabolism)
• Medroxyprogesterone Acetate (pharmacology)
• Molecular Sequence Data
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Plasmids (metabolism)
• Progesterone (pharmacology)
• Progestins (metabolism)
• Promoter Regions, Genetic
• Protein Isoforms
• Protein Structure, Tertiary
• RNA Processing, Post-Transcriptional
• RNA, Messenger (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• Time Factors
• Transcription, Genetic
• Transfection
• Vascular Endothelial Growth Factor A (metabolism)