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Pharmacological and endogenous progestins induce vascular endothelial growth factor expression in human breast cancer cells
Author(s) -
Hyder Salman M.,
Chiappetta Constance,
Stancel George M.
Publication year - 2001
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.1236
Subject(s) - endocrinology , medicine , vascular endothelial growth factor , angiogenesis , biology , messenger rna , steroid hormone , hormone , vegf receptors , biochemistry , gene
Tumor expansion is dependent on angiogenesis, which is regulated by peptide growth factors of which vascular endothelial growth factor (VEGF) is one of the most selective and potent. VEGF expression is regulated by steroid hormones in a number of systems, including T47‐D human breast cancer cells in which VEGF protein levels are elevated by progestins. In the present study, we investigated the effect of progestins on VEGF mRNA levels in human breast cancer cells. For these experiments, T47‐D cells were exposed to progestins, RNA was prepared for measurement of VEGF transcript levels by Northern blot analysis and VEGF protein in the cell culture media was measured by enzyme‐linked immunosorbent assay. Basal expression of VEGF mRNA is low in these cells, and is rapidly induced following exposure to progestins, reaching a maximum induction of 2‐ to 5‐fold between 3 and 6 hr after hormone addition. This induction was inhibited by the antiprogestin RU‐486 indicating that it is progesterone receptor (PR) dependent. Transcripts for VEGF 165 and VEGF 121 were the two major spliced forms of VEGF mRNA that were detected by reverse transcription‐polymerase chain reaction in basal and progestin‐stimulated T47‐D cells. Maximum induction of VEGF mRNA was achieved with 10 −8 M progesterone, and induction was hormone specific, as estrogens, glucocorticoids, and androgens were without effect. Actinomycin D completely abolished the induction of VEGF transcript levels by progestins, suggesting that this response involves de novo mRNA synthesis, but puromycin did not inhibit induction, suggesting that this effect does not require protein synthesis. This report demonstrates that progestins stimulate VEGF mRNA levels and raises the possibility that anti‐progestins may be useful to inhibit proliferation and metastasis in some human breast cancers by blocking VEGF production. © 2001 Wiley‐Liss, Inc.