Estradiol and Tamoxifen Regulate Endostatin Generation via Matrix Metalloproteinase Activity in Breast CancerIn vivo

Abstract

Matrix metalloproteinases (MMP) are important regulators of tumor progression and angiogenesis. MMPs generate both proangiogenic and antiangiogenic fragments, such as vascular endothelial growth factor and endostatin. The in vivo activation of MMPs and endostatin generation occur mainly in the extracellular environment by interactions of different cell types. Therefore, these processes are necessary to study in the extracellular space in vivo. Sex steroids play a dominant role in breast carcinogenesis, by largely unknown mechanisms. In the present study, we used in vivo microdialysis to directly quantify MMP-2 and MMP-9 activity and sample endostatin from both stroma (murine) and tumor (human) cells in vivo in solid MCF-7 tumors in nude mice. We found that tamoxifen in combination with estradiol increased tumor MMP-2/MMP-9 in vivo activity, endostatin levels, and decreased tumor vascularization compared with estradiol treatment only. The stroma-derived endostatin was three to five times higher than cancer cell-generated endostatin. After inhibition of MMP-2/MMP-9, endostatin levels decreased, providing evidence that these proteases are highly involved in the generation of endostatin. Our results support the previously reported concept that MMPs may serve as negative regulators of angiogenesis. The regulation of endostatin generation by modulation of MMP-2/MMP-9 activities suggests a previously unrecognized mechanism of estradiol and tamoxifen, which may have implications for the pathogenesis of breast cancer. (Cancer Res 2006; 66(9): 4789-94)

The collagenase-1 (MMP-1) gene promoter polymorphism - 1607/2G is associated with favourable prognosis in patients with colorectal cancer

“…For example, it has been suggested that the mechanism by which endothelial cell proliferation and tumour angiogenesis is inhibited is via the ability of MMP-7, -9, and -12 to convert plasminogen in to angiostatin (Dong et al, 1997). This concept was further supported by studies that demonstrated the ability of MMP-9 to generate tumstatin (a potent angiogenesis inhibitor) from type IV collagen (Hamano et al, 2003) and the MMPmediated formation of endostatin (Nilsson and Dabrosin, 2006). A beneficial role for MMP-1 has also been observed in atherosclerosis, whereby the active digestion of interstitial fibrillar collagen (types I, II, and III) by this enzyme affected cell differentiation and impaired cell migration (Lemaitre et al, 2001).…”

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

“…We have previously reported that prolonged tamoxifen treatment up-regulates MMP-9 expression in cultured MCF-7 cells in vitro and in solid MCF-7 tumors in nude mice [20,26]. To further investigate if these previous findings of increased MMP-9 levels by tamoxifen were involved in TGF-β1 regulation, experiments with this treatment were set-up.…”

“…Depending on tissue distribution and expression levels of individual MMPs and endogenous inhibitors of their activity, these enzymes may either promote or inhibit tumor progression. Lately is has been shown that up-regulation of endogenous MMPs decrease angiogenesis in tumors by the release of matrix-associated anti-angiogenic factors such as angiostatin, tumstatin, and endostatin [17][18][19][20][21]. MMPs have been associated with a positive regulation of TGF-β activity and cell responsiveness to TGF-β [22].…”

“…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].…”

“…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]. Moreover, over-expression of MMP-9 in solid MCF-7 tumors in vivo induced tumor regression and the release of extracellular endostatin [27].…”