title: An angiogenic switch in breast cancer involves estrogen and soluble vascular endothelial growth factor receptor 1.
abstract: Estrogen is involved in breast tumorigenesis, but the precise mechanisms for its oncogenic and angiogenic actions are poorly understood. Angiogenesis is regulated, in part, by these critical components: vascular endothelial growth factor (VEGF) and its two receptors (VEGFR-1 and VEGFR-2). VEGFR-2 is a positive angiogenic signal transducer, whereas VEGFR-1, especially its soluble form (soluble VEGFR-1), is a negative regulator of VEGF availability. We found that breast epithelial cells express soluble VEGFR-1 and hypothesized that because estrogen can regulate expression of members of the VEGF family, it might stimulate angiogenesis in breast cancer by decreasing expression of soluble VEGFR-1. Soluble VEGFR-1 expression decreased in estrogen receptor (ER)-positive but not in ER-negative breast cancer cell lines treated with estrogen. Pretreatment of the cells with the ER antagonist ICI 182,780 blocked the effect. The estrogen-mediated decrease in soluble VEGFR-1 expression was accompanied by a statistically significant increase in angiogenesis in vivo. Our data suggest that inhibition of soluble VEGFR-1 expression represents a novel mechanism--an estrogen-driven angiogenic switch--possibly responsible for breast carcinoma progression.
authors.affiliation: Cell Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Elkin
authors.forename: Adam
authors.initials: A
authors.lastname: Orgel
authors.forename: Hynda K
authors.initials: HK
authors.lastname: Kleinman
mesh_terms: D001943:Breast Neoplasms / Q000098:blood supply* / Q000378:metabolism*; D045744:Cell Line, Tumor; D018450:Disease Progression; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012995:Solubility; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D004967:Estrogens; D012333:RNA, Messenger; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2