Evidence for the notch signaling pathway on the role of estrogen in angiogenesis.
We have investigated the molecular mechanisms involved in 17 beta-estradiol-induced angiogenic pathway. We show here that 17 beta-estradiol promoted a 6-fold increase in Jagged1 expression and an 8-fold increase in Notch1 expression by cDNA arrays in breast cancer MCF7 cells. Interestingly, Jagged1 was abrogated by incubation with the estrogen antagonist, ICI182,780. A similar up-regulation of both Notch1 receptor and Jagged1 ligand was found in endothelial cells. Additionally, imperfect estrogen-responsive elements were found in the 5' untranslated region of Notch1 and Jagged1 genes. Treatment with 17 beta-estradiol also led to an activation of Notch signaling in MCF7 cells expressing Notch1 reporter gene or by promoting Jagged1-induced Notch signaling in coculture assays. Inoculation of MCF7 cells in 17 beta-estradiol-treated nude mice resulted in up-regulation of Notch1 expression as well as increased number of tumor microvessels in comparison to placebo-treated mice. Notch1-expressing endothelial cell cultures formed cord-like structures on Matrigel in contrast to cells expressing a dominant-negative form of Notch1, emphasizing the relevance of Notch1 pathway in vessel assembly. Finally, Notch1-expressing MCF7 cells up-regulated hypoxia-inducible factor 1 alpha gene, a well-known angiogenic factor that clustered with Notch1 gene. This study implicates Notch signaling in the cross talk between 17 beta-estradiol and angiogenesis.
Soares
R
R
Institute of Molecular Pathology and Immunology of the University of Porto, 4200 Porto, Portugal. raquel.soares@ipatimup.pt
Balogh
G
G
Guo
S
S
Gärtner
F
F
Russo
J
J
Schmitt
F
F
D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply* / Q000378:metabolism; D002135:Calcium-Binding Proteins; D045744:Cell Line, Tumor; D004967:Estrogens / Q000494:pharmacology / Q000502:physiology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D009368:Neoplasm Transplantation / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015854:Up-Regulation
D002135:Calcium-Binding Proteins; D004967:Estrogens; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D000072099:Serrate-Jagged Proteins; D014157:Transcription Factors