title: Estradiol-induced vascular endothelial growth factor-A expression in breast tumor cells is biphasic and regulated by estrogen receptor-alpha dependent pathway.
abstract: Estrogens have been shown to regulate vascular endothelial growth factor-A (VEGF-A) for physiological and patho-physiological functions. However, estrogen action on VEGF-A mRNA expression has not been completely elucidated. We have identified two phases of activation of VEGF-A mRNA transcription, one early and one late response, induced by 17beta-estradiol (17beta-E2) in ER+ MCF-7 breast tumor cells, depending upon the length of exposure. VEGF-A mRNA level was significantly higher than control in tumor cells after 2 h of 17beta-E2 exposure. Furthermore this induction was not inhibited by cycloheximide, indicating that it was a direct effect of estrogen. In contrast VEGF-A mRNA expression was back at basal level in MCF-7 cells exposed to 17beta-E2 for 6 h. However, expression levels were again significantly augmented after 24 h of exposure, and this induction was unaltered by cycloheximide indicating that de novo protein synthesis was not required and like early response, it was a direct effect of estrogen. The antiestrogen ICI 182,780 was a pure antagonist for the early response phase of VEGF-A mRNA induction, but it had partial but significant effect on the late response phase, further suggesting that both early and late phases were ER dependent. In human mammary epithelial cells (HMEC) lacking estrogen receptor (ER-alpha) the early and late response phase of VEGF-A mRNA induction in response to 17beta-E2 was not found, but significant inductions were seen in the early and late phases when ER-alpha transfected HMEC were exposed to 17beta-E2 for 2 or 24 h. Taken together, these studies suggest that VEGF-A is an estrogen responsive gene and modulation of this gene expression by estrogen is biphasic and can be mediated through ER-alpha dependent pathway.
authors.affiliation: Cancer Research Unit, V.A. Medical Center and Division of Oncology and Hematology, Department of Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Krishanu
authors.initials: K
authors.lastname: Sengupta
authors.forename: Snigdha
authors.initials: S
authors.lastname: Banerjee
authors.forename: Neela
authors.initials: N
authors.lastname: Saxena
authors.forename: Sushanta K
authors.initials: SK
authors.lastname: Banerjee
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D011960:Receptors, Estrogen / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D009363:Neoplasm Proteins; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011960:Receptors, Estrogen; D042461:Vascular Endothelial Growth Factor A; D000077267:Fulvestrant; D004958:Estradiol; D003513:Cycloheximide