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Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) (R.S., F.G., F.S.); Medical Faculty (R.S., F.S.), University of Porto; and Molecular Pathology Unit (R.S.), Portuguese Institute of Oncology, 4200 Porto, Portugal; Breast Cancer Research Lab (G.B., S.G., J.R.), Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111; and Pathology Department (F.G.), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), 4050 Porto, Portugal
Address all correspondence and requests for reprints to: Raquel Soares, MSc, Ph.D., IPATIMUP, R. Roberto Frias s/n, 4200 Porto, Portugal. E-mail: raquel.soares{at}ipatimup.pt.
We have investigated the molecular mechanisms involved in 17ß-estradiol-induced angiogenic pathway. We show here that 17ß-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 17ß-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 17ß-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
gene, a well-known angiogenic factor that clustered with Notch1 gene. This study implicates Notch signaling in the cross talk between 17ß-estradiol and angiogenesis.
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