title: Resveratrol inhibits heregulin-beta1-mediated matrix metalloproteinase-9 expression and cell invasion in human breast cancer cells.
abstract: The growth factor heregulin-beta1 (HRG-beta1), which is expressed in breast cancer, activates the HER-2 signaling pathway through induction of heterodimeric complexes of HER-2 with HER-3 or HER-4. It has been shown in many studies that HRG-beta1 induces the tumorigenicity and metastasis of breast cancer cells. Matrix metalloproteinase (MMP) 9 is a key enzyme in the degradation of extracellular matrices, and its expression may be dysregulated in breast cancer invasion and metastasis. Resveratrol, a major component in grape, exhibited potential anticarcinogenic activities in both in vitro and in vivo studies. However, the inhibitory effect of resveratrol on HER-2-mediated expression of MMP-9 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 and 10 microM). The expression activity of MMP-9 was measured by zymogram analysis. Phosphorylated levels of HER-2 and mitogen-activated protein kinase (MAPK)/ERK were measured by Western blot analysis. Total actin was used as internal control for protein expression. HRG-beta1 induced the phosphorylation of HER-2/neu receptor and MMP-9 expression in human breast cancer MCF-7 cells. Resveratrol significantly inhibited HRG-beta1-mediated MMP-9 expression in human breast cancer cells. MEK inhibitor induced a marked reduction in MMP-9 expression, and it suggested that ERK1/2 cascade could play an important role in HRG-beta1-mediated MMP-9 expression. Furthermore, resveratrol significantly suppressed HRG-beta1-mediated phosphorylation of ERK1/2 and invasion of breast cancer cells. However, resveratrol had negligible effects on either HRG-beta1-mediated phosphorylation of HER-2 receptor or expression of the tissue inhibitor of MMP, tissue inhibitor metalloproteinase protein 1. Taken together, our results suggest that resveratrol inhibited MMP-9 expression in human breast cancer cells. The inhibitory effects of resveratrol on MMP-9 expression and invasion of breast cancer cells are, in part, associated with the down-regulation of the MAPK/ERK signaling pathway.
authors.affiliation: Biomedical Science Laboratory, Department of Nutrition, China Medical University, Taichung 40402, Taiwan, ROC. vincenttang@mail.cmu.edu.tw
authors.forename: Feng-Yao
authors.initials: FY
authors.lastname: Tang
authors.forename: En-Pei Isabel
authors.initials: EP
authors.lastname: Chiang
authors.forename: Ya-Chi
authors.initials: YC
authors.lastname: Sun
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology*; D020890:Neuregulin-1 / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005419:Flavonoids; D020780:Matrix Metalloproteinase 9; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D000077185:Resveratrol; D013267:Stilbenes; D019714:Tissue Inhibitor of Metalloproteinases; C087230:heregulin beta1; C508053:ERBB2 protein, human; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one