MMP-2 and MMP-9 activity is regulated by estradiol and tamoxifen in cultured human breast cancer cells

Abstract

Sex steroids play a dominant role in breast carcinogenesis by still largely unknown mechanisms. Matrix metalloproteinases (MMPs) have been extensively studied in the context of matrix biology but it is not known if sex steroids affect MMPs in breast cancer. MMPs degrade extracellular matrix components enabling tumor cell invasion and metastasis, but may also regulate the bioavailability of a variety of biologically active molecules such as anti-angiogenic fragments, which may be beneficial for the host. This study shows that estradiol and tamoxifen regulate MMP-2 and MMP-9 as well as TIMP-1 and TIMP-2 in ER + PR + human breast cancer cells. The main finding was a significant effect of tamoxifen exposure, which increased intracellular and secreted protein levels whereas estradiol induced a significant decrease. The overall net effect of these alterations resulted in increased MMP-2/MMP-9 activity by tamoxifen treatment, which also significantly increased extracellular endostatin levels. We conclude that estradiol and tamoxifen have the ability to modulate MMP-2/MMP-9 activity, and endostatin levels in human breast cancer in vitro. The results suggest a possible role of MMP modulation associated with a generation of anti-angiogenic fragments in the therapeutic effect of tamoxifen in breast cancer.

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

“…Garvin et al (2006) also demonstrated that similar events also occurred in ex vivo cultured normal human breast tissue (Garvin et al, 2006). In addition, MMP-9 are closely associated with tumor growth, invasion and metastasis (Versteeg et al, 2008) and estrogen has been shown to regulate the activity of MMP-2 and MMP-9 in breast cancer cells (Nilsson et al, 2007).…”

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

“…2B) 2D). It should be stated that the fluorogenic substrate used in the activity assay may also be cleaved by MMP-2; however, as we have showed previously, the induced levels of active MMP-2 in MCF-7 cells are considerably lower than the levels of active MMP-9 [26].…”

“…In this regard, we have previously shown tamoxifen may also alter the extracellular levels of natural inhibitors of MMPs [26]. Therefore, we verified if the altered MMP-9 protein levels also affected the extracellular physiological MMP activity using a substrate activity assay.…”

“…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.…”

“…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].…”