The heregulin β-1 (HRG-β1) growth factor, expressed in breast cancer tumors, activates the HER-2 signaling pathway through induction of heterodimeric complexes of HER-2 with HER-3 or HER-4. It has been shown that HRG-β1 induces tumorigenicity and metastasis of breast cancer cells in many studies. Among all targeted genes of HER-2 signaling pathway, matrix metalloproteinase-9 (MMP-9) is a key enzyme in degradation of extracellular matrices and its expression may be dysregulated in the breast cancer invasion and metastasis. Resveratrol, a major component in grape, exhibited potential anti-carcinogenic activities in both in vitro and in vivo studies. However, the inhibitory effect of resveratrol on HER-2 mediated MMP-9 activation has not been demonstrated yet.

In the present study, we investigated the anti-invasive mechanism of resveratrol in human breast cancer cells. Human breast cancer MCF-7 cells were exposed to resveratrol (2, 5, 10 μM). Enzymatic activity of MMP-9 was measured by zymographic analysis. Phosphorylated levels of HER-2 and mitogen-activated protein kinase (MAPK)/ ERK signaling pathways were measured by Western blotting analysis. Total HER-2 and ERK were used as internal controls for level of protein expression. HRG-β1 induced phosphorylation of HER-2/neu receptor and MMP-9 in human breast cancer MCF-7 cells. Resveratrol significantly inhibited HRG-β1- mediated MMP-9 activation in human breast cancer cells. MEK inhibitor induced a marked reduction in MMP-9 activity, and it suggested that ERK1/2 cascade could play an important role in HRG-β1 mediated MMP-9 activation. Furthermore, resveratrol significantly suppressed HRG-β1 mediated phosphorylation of ERK1/2 and invasion of breast cancer cells. However, resveratrol had negligible effects on either HRG-β1-mediated phosphorylation of HER-2 receptor or expression of tissue inhibitor of MMP, tissue inhibitor metalloproteinase protein -1 (TIMP-1).

Take together; our results suggest that resveratrol inhibited MMP-9 activity in human breast cancer cells. The inhibitory effects of resveratrol on MMP-9 activation and invasion of breast cancer cells are in part associated with the down-regulation of MAPK/ERK signaling pathway.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA