title: Hypoxia and estrogen are functionally equivalent in breast cancer-endothelial cell interdependence.
abstract: BACKGROUND
  Rapid breast tumor development relies on formation of new vasculature to supply the growing malignancy with oxygenated blood. Previously we found that estrogen aided in this neovasculogenesis via recruitment of bone marrow derived endothelial progenitor cells (BM-EPCs), leading to increased vessel formation and vascular endothelial growth factor (VEGF) production in vivo. However, the cellular mechanism of this induction and the signaling pathways involved need elucidation.
  
  
  RESULTS
  Using the murine mammary cell line TG1-1 we observed estrogen (E2) lead to an up regulation of hypoxia inducible factor-1 (HIF-1), an effect abrogated by the anti-estrogen Fulvestrant and the HIF-1 inhibitor YC-1 (3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole) suggesting the interchangeability of hypoxia and estrogen mediated effects. Estrogen modulation of HIF-1 and subsequent effects on endothelial cells is dependent on the Akt/PI3K pathway and protein synthesis as validated by the use of the inhibitors wortmannin and cycloheximide which abrogated estrogen's effects respectively. Estrogen treated TG1-1 cells secreted higher levels of VEGF which were comparable to secreted levels from cells grown under hypoxic conditions. Soluble factors in conditioned media from E2 treated breast cancer cells also lead to migration and tube formation of human umbilical vein endothelial cells (HUVEC) in vitro.
  
  
  CONCLUSIONS
  Our data provide evidence that estrogen signaling mediates the tumor vasculogenic process required for breast cancer progression and involves a key regulator of the hypoxia signaling pathway. Further, hypoxia and estrogen are interchangeable as both similarly modulate epithelial-endothelial cell interaction.
authors.affiliation: Department of Microbiology and Immunology, New York Medical College, Valhalla, NY, 10595, USA. raj_tiwari@nymc.edu.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: George
authors.forename: Shilpi
authors.initials: S
authors.lastname: Rajoria
authors.forename: Robert
authors.initials: R
authors.lastname: Suriano
authors.forename: Abraham
authors.initials: A
authors.lastname: Mittleman
authors.forename: Raj K
authors.initials: RK
authors.lastname: Tiwari
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D004967:Estrogens / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D004967:Estrogens; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D019869:Phosphatidylinositol 3-Kinases