Effects of oestradiol and tamoxifen on VEGF, soluble VEGFR-1, and VEGFR-2 in breast cancer and endothelial cells

Abstract

Angiogenesis is regulated by the balance between pro-and antiangiogenic factors. Vascular endothelial growth factor (VEGF), acting via the receptors VEGFR-1 and VEGFR-2, is a key mediator of tumour angiogenesis. The soluble form of the VEGF receptor-1 (sVEGFR-1) is an important negative regulator of VEGF-mediated angiogenesis. The majority of breast cancers are oestrogen dependent, but it is not fully understood how oestrogen and the antioestrogen, tamoxifen, affect the balance of angiogenic factors. Angiogenesis is a result of the interplay between cancer and endothelial cells, and sex steroids may exert effects on both cell types. In this study we show that oestradiol decreased secreted sVEGFR-1, increased secreted VEGF, and decreased the ratio of sVEGFR-1/ VEGF in MCF-7 human breast cancer cells. The addition of tamoxifen opposed these effects. Moreover, human umbilical vein endothelial cells (HUVEC) incubated with supernatants from oestradiol-treated MCF-7 cells exhibited higher VEGFR-2 levels than controls. In vivo, MCF-7 tumours from oestradiol þ tamoxifen-treated nude mice exhibited decreased tumour vasculature. Our results suggest that tamoxifen and oestradiol exert dual effects on the angiogenic environment in breast cancer by regulating cancer cell-secreted angiogenic ligands such as VEGF and sVEGFR-1 and by affecting VEGFR-2 expression of endothelial cells.

Synergistic Effects of Tamoxifen and Tranilast on VEGF and MMP-9 Regulation in Cultured Human Breast Cancer Cells

“…Tamoxifen is a competitive antagonist of estrogen, but seems to have antiangiogenic effects independent of, and in addition to, estrogen receptor content or its anti-estrogen effects (Kousidoua et al, 2008). It have been reported that tamoxifen treatment of breast cancer, induces an antiangiogenic response by an efficient decrease of VEGF both in vitro and in vivo (Garvin and Dabrosin, 2003;Garvin et al, 2005;Nilsson and Dabrosin, 2006;Kumar et al, 2013;Rajput et al, 2013).…”

Estradiol Increases IL-8 Secretion of Normal Human Breast Tissue and Breast Cancer In Vivo

“…This does not, however, rule out an estrogen-dependent regulation of IL-8 in less metastatic breast cancer cells. We have previously shown that VEGF secretion is increased by estradiol in MCF-7 cells although these cells express VEGF at very low levels (40,41). Very few studies have investigated direct effects on IL-8 secretion after estrogen exposure in hormone-dependent breast cancer models.…”

Tamoxifen decreases extracellular TGF-β1 secreted from breast cancer cells — A post-translational regulation involving matrix metalloproteinase activity

“…Anti-estrogens, such as the synthetic, non-steroidal compound tamoxifen, and aromatase inhibitors, are cornerstones in the medical treatment of breast cancer. We have previously reported that tamoxifen treatment of experimental breast cancer, both in vitro and in vivo, induces an anti-angiogenic response [20,[24][25][26]. We recently showed that tamoxifen significantly up-regulated the expression and activity of MMP-9, whereas estradiol treatment decreased MMP-9 activity levels [20].…”