Exp Mol Med.  2012 Aug;44(8):473-482.

A functional comparison between the HER2high/HER3 and the HER2low/HER3 dimers on heregulin-beta1-induced MMP-1 and MMP-9 expression in breast cancer cells

• Kim S
• Han J
• Shin I
• Kil WH
• Lee JE
• Nam SJ

Abstract

Overexpression of HER2 correlates with more aggressive tumors and increased resistance to cancer chemotherapy. However, a functional comparison between the HER2high/HER3 and the HER2low/HER3 dimers on tumor metastasis has not been conducted. Herein we examined the regulation mechanism of heregulin-beta1 (HRG)-induced MMP-1 and -9 expression in breast cancer cell lines. Our results showed that the basal levels of MMP-1 and -9 mRNA and protein expression were increased by HRG treatment. In addition, HRG-induced MMP-1 and -9 expression was significantly decreased by MEK1/2 inhibitor, U0126 but not by phosphatidylinositol 3-kinase (PI-3K) inhibitor, LY294002. To confirm the role of MEK/ERK pathway on HRG-induced MMP-1 and -9 expression, MCF7 cells were transfected with constitutively active adenoviral-MEK (CA-MEK). The level of MMP-1 and -9 expressions was increased by CA-MEK. MMP-1 and -9 mRNA and protein expressions in response to HRG were higher in HER2 overexpressed cells than in vector alone. The phosphorylation of HER2, HER3, ERK, Akt, and JNK were also significantly increased in HER2 overexpressed MCF7 cells compared with vector alone. HRG-induced MMP-1 and -9 expressions were significantly decreased by lapatinib, which inhibits HER1 and HER2 activity, in both vector alone and HER2 overexpressed MCF7 cells. Finally, HRG-induced MMP-1 and MMP-9 expression was decreased by HER3 siRNA overexpression. Taken together, we suggested that HRG-induced MMP-1 and MMP-9 expression is mediated through HER3 dependent pathway and highly expressed HER2 may be associated with more aggressive metastasis than the low expressed HER2 in breast cancer cells.

Keyword

breast neoplasms; HER2 protein, human; heregulin-beta1; matix metalloproteinase 1; matrix metalloproteinase 9; mitogen-activated protein kinase 1; neoplasm metastasis

MeSH Terms

Breast Neoplasms/enzymology/*genetics/*metabolism
Butadienes/pharmacology
Cell Line, Tumor
Dose-Response Relationship, Drug
Enzyme Inhibitors/pharmacology
Female
Gene Expression
Gene Expression Regulation, Neoplastic/drug effects
Humans
MAP Kinase Signaling System
MCF-7 Cells
Matrix Metalloproteinase 1/*genetics/metabolism
Matrix Metalloproteinase 9/*genetics/metabolism
Neuregulin-1/*pharmacology
Nitriles/pharmacology
Phosphatidylinositol 3-Kinases/metabolism
Protein Kinase Inhibitors/pharmacology
Protein Multimerization
Proto-Oncogene Proteins c-akt/metabolism
Quinazolines/pharmacology
Receptor, erbB-2/genetics/*metabolism
Receptor, erbB-3/*metabolism