scholarly journals Xenoestrogens modulate vascular endothelial growth factor secretion in breast cancer cells through an estrogen receptor-dependent mechanism

2007 ◽  
Vol 196 (2) ◽  
pp. 399-412 ◽  
Author(s):  
Hélène Buteau-Lozano ◽  
Guillaume Velasco ◽  
Monique Cristofari ◽  
Patrick Balaguer ◽  
Martine Perrot-Applanat
Keyword(s):  
Breast Cancer ◽  
Vascular Endothelial Growth Factor ◽  
Estrogen Receptor ◽  
Growth Factor ◽  
Breast Cancer Cells ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Endothelial Growth Factor ◽  
Dependent Mechanism ◽  
Mcf 7

Environmental chemicals may affect human health by disrupting endocrine function. Their possible role in the mammary gland and breast tumors is still unknown. Previous studies have demonstrated that vascular endothelial growth factor (VEGF), a key factor in angiogenesis and tumor progression, is an estrogen-regulated gene. We analyzed whether VEGF expression is regulated by different xenoestrogens in several breast cancer cells, MELN (derived from MCF-7) and MELP (derived from MDA-MB-231) and stably expressing estrogen receptor α (ERα); these cell lines stably express estrogen response element (β-globin)-luciferase. Genistein, bisphenol A (BPA), 4-(tert-octyl)phenol (OP), dieldrin, and several phthalates, including benzyl butyl phthalate (BBP) and di-ethyl-2-hexyle phthalate (DEHP), were first shown to be estrogenic. These compounds induced a dose-dependent increase of VEGF secretion in MELN and MCF-7 cells; maximal effect was observed at 1–10 μM non-cytotoxic concentrations and was inhibited by the antiestrogen ICI 182 780. VEGF increase was not observed in ERα-negative MDA-MB-231 cells. Most substances increased VEGF transcript levels in MELN cells. In contrast, γ-hexachlorocyclohexane, vinclozolin, and the phthalates (mono-n-butyl ester phthalic acid, di-isononyle phthalate, and di-isodecyle phthalate) were ineffective on both VEGF secretion and estrogenic luciferase induction in these cell lines. Specific kinase inhibitors PD98059, SB203580, or LY294002 suppressed the xenoestrogen-induced VEGF response, suggesting activation of MEK, p38 kinase, and phosphatidylinositol-3-kinase pathways. Our in vitro results show for the first time that genistein and xenoestrogens (BPA, OP, dieldrin, BBP, and DEHP at high concentrations) up-regulate VEGF expression in MELN cells by an ER-dependent mechanism. Since VEGF increases capillary permeability and breast tumor angiogenesis in vivo, the physiological relevance of these findings is discussed.

scholarly journals Loss of Epigenetic Kruppel-like Factor 4 Histone Deacetylase (KLF-4-HDAC)-mediated Transcriptional Suppression Is Crucial in Increasing Vascular Endothelial Growth Factor (VEGF) Expression in Breast Cancer

2013 ◽  
Vol 288 (38) ◽  
pp. 27232-27242 ◽  
Author(s):  
Alpana Ray ◽  
Mohamed Alalem ◽  
Bimal K. Ray
Keyword(s):  
Breast Cancer ◽  
Vascular Endothelial Growth Factor ◽  
Transcription Factor ◽  
Growth Factor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Angiogenic Factor ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) is recognized as an important angiogenic factor that promotes angiogenesis in a series of pathological conditions, including cancer, inflammation, and ischemic disorders. We have recently shown that the inflammatory transcription factor SAF-1 is, at least in part, responsible for the marked increase of VEGF levels in breast cancer. Here, we show that SAF-1-mediated induction of VEGF is repressed by KLF-4 transcription factor. KLF-4 is abundantly present in normal breast epithelial cells, but its level is considerably reduced in breast cancer cells and clinical cancer tissues. In the human VEGF promoter, SAF-1- and KLF-4-binding elements are overlapping, whereas SAF-1 induces and KLF-4 suppresses VEGF expression. Ectopic overexpression of KLF-4 and RNAi-mediated inhibition of endogenous KLF-4 supported the role of KLF-4 as a transcriptional repressor of VEGF and an inhibitor of angiogenesis in breast cancer cells. We show that KLF-4 recruits histone deacetylases (HDACs) -2 and -3 at the VEGF promoter. Chronological ChIP assays demonstrated the occupancy of KLF-4, HDAC2, and HDAC3 in the VEGF promoter in normal MCF-10A cells but not in MDA-MB-231 cancer cells. Co-transfection of KLF-4 and HDAC expression plasmids in breast cancer cells results in synergistic repression of VEGF expression and inhibition of angiogenic potential of these carcinoma cells. Together these results identify a new mechanism of VEGF up-regulation in cancer that involves concomitant loss of KLF-4-HDAC-mediated transcriptional repression and active recruitment of SAF-1-mediated transcriptional activation.

scholarly journals Vascular Endothelial Growth Factor Receptor-2 Expression Is Induced by 17β-Estradiol in ZR-75 Breast Cancer Cells by Estrogen Receptor α/Sp Proteins

Endocrinology ◽  
2006 ◽  
Vol 147 (7) ◽  
pp. 3285-3295 ◽  
Author(s):  
Kelly J. Higgins ◽  
Shengxi Liu ◽  
Maen Abdelrahim ◽  
Kyungsil Yoon ◽  
Kathryn Vanderlaag ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Chromatin Immunoprecipitation ◽  
Breast Cancer Cells ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
Rich Region ◽  
17Β Estradiol ◽  
Endothelial Growth Factor

Vascular endothelial growth factor receptor-2 kinase insert domain receptor (VEGFR2/KDR) is critical for angiogenesis, and VEGFR2 mRNA and protein are expressed in ZR-75 breast cancer cells and induced by 17β-estradiol (E2). Deletion analysis of the VEGFR2 promoter indicates that the proximal GC-rich region is required for both basal and hormone-induced transactivation, and mutation of one or both of the GC-rich motifs at −58 and −44 results in loss of transactivation. Electrophoretic mobility shift and chromatin immunoprecipitation assays show that Sp1, Sp3, and Sp4 proteins bind the GC-rich region of the VEGFR2 promoter. Results of the chromatin immunoprecipitation assay also demonstrate that ERα is constitutively bound to the VEGFR2 promoter and that these interactions are not enhanced after treatment with E2, whereas ERα binding to the region of the pS2 promoter containing an estrogen-responsive element is enhanced by E2. RNA interference studies show that hormone-induced activation of the VEGFR2 promoter constructs requires Sp3 and Sp4 but not Sp1, demonstrating that hormonal activation of VEGFR2 involves a nonclassical mechanism in which ERα/Sp3 and ERα/Sp4 complexes activate GC-rich sites where Sp proteins but not ERα bind DNA. These results show for the first time that Sp3 and Sp4 cooperatively interact with ERα to activate VEGFR2 and are in contrast to previous results showing that several hormone-responsive genes are activated by ERα/Sp1 in breast cancer cell lines.

scholarly journals Up-regulation of Vascular Endothelial Growth Factor C in Breast Cancer Cells by Heregulin-β1

2002 ◽  
Vol 278 (8) ◽  
pp. 5750-5759 ◽  
Author(s):  
Pei-Wen Tsai ◽  
Shine-Gwo Shiah ◽  
Ming-Tsan Lin ◽  
Cheng-Wen Wu ◽  
Min-Liang Kuo
Keyword(s):  
Breast Cancer ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Vascular Endothelial ◽  
Factor C ◽  
Endothelial Growth Factor
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