Phosphatidylinositol 3′ Kinase (PI3K), A Crucial Regulator of Epidermal Growth Factor Receptor (EGFR) Modulated MMP-2, MMP-9 and MT1-MMP Expression in Breast Cancer Cells

Tumour metastasis is responsible for the majority of mortalities in breast cancer. Increased tumour
invasion and poorer prognosis has been reported in breast cancers with elevated epidermal growth
factor receptor (EGFR) activity. Increased expression of the matrix metalloproteinases (MMPs) MMP-
2, MMP-9 and MT1-MMP show significant correlation with increased metastasis and poorer survival in
breast cancer patients. In our present study we investigated the role of phosphatidylinositol 3′ kinase
(PI3K) in EGFR mediated regulation of MMPs in breast cancer using the invasive human breast
adenocarcinoma cell line MDA-MB-231 as a model. PI3K phosphorylation is increased upon
interaction of EGFR with its cognate ligand EGF. Inhibition of PI3K with the PI3K inhibitor LY294002
hinders EGFR modulated upregulation of MMP-2, MMP-9 and MT1-MMP at both protein and mRNA
levels. PI3K thus appears to be crucially involved in EGFR mediated signalling cascades which
promote elevated MMP-2, MMP-9 and MT1-MMP expression in MDA-MB-231 cells. Our findings
elucidate the importance of PI3K mediated signalling in modulation of invasive potential, via regulation
of MMP-2, MMP-9 and MT1-MMP expression, in breast cancer cells upon EGFR activation and
suggest that the use of PI3K inhibitors might have therapeutic value in inhibiting tumour invasion (thus
improving patient survival) in breast cancers with elevated and aberrant EGFR activity.