Document Detail

Proliferation of endothelial and tumor epithelial cells by progestin-induced vascular endothelial growth factor from human breast cancer cells: paracrine and autocrine effects.
MedLine Citation:
PMID:  15845615     Owner:  NLM     Status:  MEDLINE    
Angiogenesis, the formation of new blood vessels, is essential for tumor expansion, and vascular endothelial growth factor (VEGF) is one of the most potent angiogenic growth factors known. We have previously shown that natural and synthetic progestins, including those used in hormone replacement therapy and oral contraception, induce the synthesis and secretion of VEGF in a subset of human breast cancer cells in a progesterone receptor-dependent manner. We now report that conditioned medium from progestin-treated breast tumor cells can induce the proliferation of endothelial cells in a paracrine manner and induce the proliferation of tumor epithelial cells in a paracrine and an autocrine manner. The use of an anti-VEGF antibody and SU-1498, an inhibitor of VEGF receptor-2 (VEGFR-2 or flk/kdr) tyrosine kinase activity, demonstrated that these effects involve interactions between VEGF and VEGFR-2. Also, blockage of progestin-induced VEGF by the antiprogestin RU-486 (mifepristone) eliminated VEGF-induced proliferative effects. The ability of VEGF to increase the proliferation of endothelial cells and tumor cells, including those that do not release VEGF in response to progestins, suggests that these effects are mediated by amplification of the progestin signal, which culminates in angiogenesis and tumor growth. These novel findings suggest that targeting the release of VEGF from tumor epithelial cells as well as blocking interactions between VEGF and VEGFR-2 on both endothelial and tumor epithelial cells may facilitate the development of new antiangiogenic therapies for progestin-dependent breast tumors. Furthermore, these data indicate that it would be useful to develop selective progesterone receptor modulators that prevent the release of angiogenic growth factors from breast cancer cells.
Yayun Liang; Salman M Hyder
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, P.H.S.     Date:  2005-04-21
Journal Detail:
Title:  Endocrinology     Volume:  146     ISSN:  0013-7227     ISO Abbreviation:  Endocrinology     Publication Date:  2005 Aug 
Date Detail:
Created Date:  2005-07-12     Completed Date:  2005-09-26     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0375040     Medline TA:  Endocrinology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3632-41     Citation Subset:  AIM; IM    
Dalton Cardiovascular Research Center and Biomedical Sciences, University of Missouri, Columbia, Missouri 65211, USA.
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MeSH Terms
Breast Neoplasms
Cell Division
Cell Line, Tumor
Cell Survival / drug effects
Endothelium, Vascular / cytology,  pathology,  physiology*
Enzyme-Linked Immunosorbent Assay
Gene Expression Regulation, Neoplastic
Medroxyprogesterone Acetate / pharmacology
Progestins / physiology*
Reverse Transcriptase Polymerase Chain Reaction
Umbilical Veins
Vascular Endothelial Growth Factor A / biosynthesis*
Vascular Endothelial Growth Factor Receptor-1 / genetics*
Vascular Endothelial Growth Factor Receptor-2 / genetics*
Grant Support
Reg. No./Substance:
0/Progestins; 0/Vascular Endothelial Growth Factor A; 71-58-9/Medroxyprogesterone Acetate; EC Endothelial Growth Factor Receptor-1; EC Endothelial Growth Factor Receptor-2

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