ERK/MAPK pathways play critical roles in EGFR ligands-induced MMP1 expression

Activation of epidermal growth factor receptor (EGFR)-induced signaling pathways has been correlated with tumor progression, invasion and metastasis in a variety of cancers including breast carcinoma, but the underlying mechanism is not well understood. Matrix metalloproteinases (MMPs) have been implicated in cancer invasion and metastasis for their extracellular matrix (ECM)-proteolytic activity. However, the correlation of EGFR pathway with MMP expression in breast cancer has not been established. The aim of this study was to elucidate the interaction between EGFR ligands and their signaling pathway and MMP expression which might be closely related with breast cancer pathogenesis. We investigated the effect of EGF ligands on the MMP1 expression in SK-BR3 cell lines using RT-PCR, Western blot, ELISA and EMSA. Treatments with EGFR ligands, EGF and TGF-α enhanced MMP1 expression at the level of both transcription and translation in SK-BR3 breast cancer cells. EGF and TGF-α treatment resulted in phosphorylation of EGFR, and consequent activation of ERK1/2 pathway. Tyrosine kinase inhibitors of HER family, erlotinib, lapatinib and canertinib suppressed EGF-ligands mediated MMP1 overexpression. The specific MEK inhibitor, U0126, significantly blocks EGF and TGF-α-mediated ERK1/2 activation and subsequent MMP1 induction in SK-BR3 cells. Inhibition of the Akt pathway with LY294002 paradoxically augmented MMP1 expression by reciprocal activation of ERK1/2 pathway. These data suggest that invasive potential of SK-BR3 cell would be affected by these drugs by suppression of EGFR ligands-induced MMP1 expression.