Overexpression of HER2 correlates with more aggressive
tumors and increased resistance to
cancer chemotherapy. However, a functional comparison between the HER2(high)/HER3 and the HER2(low)/HER3 dimers on
tumor metastasis has not been conducted. Herein we examined the regulation mechanism of
heregulin- β1 (
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.