An angiogenic switch in breast cancer involves estrogen and soluble vascular endothelial growth factor receptor 1.
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.
Elkin
Michael
M
Cell Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Orgel
Adam
A
Kleinman
Hynda K
HK
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
D004967:Estrogens; D012333:RNA, Messenger; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2