Epidermal growth factor receptor-mediated regulation of matrix metalloproteinase-2 and matrix metalloproteinase-9 in MCF-7 breast cancer cells
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In breast cancer, increased epidermal growth factor receptor (EGFR) expression and phosphorylation have been correlated with increased invasive potential and poor prognosis. Interaction of EGFR with its ligand epidermal growth factor (EGF) activates cellular signalling cascades promoting tumour invasion. Matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) are upregulated in most cancers and play crucial roles in modulating invasion and metastasis. EGFR-mediated regulation of MMP-2 and MMP-9 in breast cancer was investigated using metastatic human breast ductal carcinoma cell line MCF-7. Culture of MCF-7 cells on 1 µg/ml EGF-coated culture dishes for 24 h led to appreciable increase in MMP-2 and MMP-9 expression and activity. Expression of membrane type-1 matrix metalloproteinase (MT1-MMP) and focal adhesion kinase (FAK), phosphorylation of EGFR and phosphatidylinositol 3′ kinase (PI3K), and nuclear translocation of EGFR and cellular migration were also appreciably increased. Targeting EGFR–EGF interactions by treatment of MCF-7 cells with anti-EGFR monoclonal antibodies prior to culture on EGF prevented appreciable upregulation of MMP-2 and MMP-9 expression and activity. Increased expression of MT1-MMP and FAK, phosphorylation of EGFR and PI3K and enhanced cell migration were also inhibited. Treatment of cells with PI3K inhibitor LY294002 prevented upregulation of MMP-2 and MMP-9 indicating that EGFR-mediated signalling for MMP regulation occurs through PI3K. As increased EGFR activity has been observed in highly invasive breast cancers, targeting EGFR–EGF interactions might render such cancers less invasive by inhibiting EGFR-mediated upregulation of MMP-2 and MMP-9 and therefore could be of importance in their clinical management.
KeywordsBreast cancer Epidermal growth factor receptor (EGFR) Matrix metalloproteinase-2 (MMP-2) Matrix metalloproteinase-9 (MMP-9) Phosphatidylinositol 3′ kinase (PI3K)
We are thankful to the Department of Science and Technology, Government of West Bengal [903(Sanc.)/ST/P/S&T/9G-19/2013] for financial support and to Rev. Fr. Dr. Dominic Savio S.J., Principal, St. Xavier’s College (Autonomous), Kolkata for providing facilities, support and encouragement.
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflict of interest.
Research involving human participants and/or animals
This article does not contain any studies with human participants or animals performed by any of the authors.
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