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.