Abstract: Objective To investigate whether epidermal growth factor (EGF) regulates expression of voltage-gated sodium channel (VGSC) subtype of Nav1.5 as well as the possible intracellular pathway through which EGF may influences Nav1.5 expression. Methods Matrigel test, immunofluorescence, real-time fluorogentic quantitative PCR ( RFQ-PCR) and Western blot were used to investigate the level and intracellular distribution of EGF receptor (EGFR) , Nav1.5 protein, the effect of EGF on Nav1.5 mRNA expression and possible effect of PI3K on EGF enhancement of MDA-MB-231 cell invasion. Results MDA-MB-231 cells significantly expressed higher EGFR and Nav1.5 protein. EGF increased invasion of the cells approximately 51% ± 2.6% （P﹤0.05）, and Tetrodotoxin (TTX) , the blocker of VGSC, suppressed the effect of EGF on the cell invasion (P﹤0.05) . The level of Nav1.5 mRNA and protein were increased by EGF treatment by 128 ± 4 times and 39% ± 4% (P﹤0.05 for both）, respectively. Wortmannin , the inhibitor of PI3K, significantly reduced the EGF-induced increase of both Nav1.5mRNA and protein, and also decresed MDA-MB-231 cell invasion induced by EGF through Nav1.5. Conclusions EGF upregulated Nav1.5 mRNA and protein expression which promoted the invasion of strongly metastatic breast cancer MDA-MB-231 cells, and PI3K was found to be involved in the signaling cascade of EGF-induced VGSC/Nav1.5 expression.