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Several recent studies have suggested that the acquisition of the multidrug resistance (MDR) phenotype is associated with elevated invasion and metastasis of tumor cells. P-glycoprotein (P-gp), the major determinant in the generation of the MDR phenotype, was reported to be correlated with a more aggressive phenotype and poor prognosis in many forms of malignancies. However, a clear understanding of the association is still lacking. We previously showed that Anxa2, a calcium-dependent phospholipid-binding protein, interacts with P-gp and contributes to the invasiveness of MDR breast cancer cells. In the present study, a strong positive correlation between MDR1 and Anxa2 mRNA expression in invasive breast cancer tissues during cancer progression was observed. In addition, exposure to adriamycin significantly enhanced motility in breast cancer cells and increased levels of P-gp and Anxa2. Moreover, inhibition of P-gp activity, using selective P-gp modulators, was found to significantly inhibit the invasive capacity of MCF-7/ADR cells without affecting the interaction and co-localization between P-gp and Anxa2. However, suppression of P-gp pump activity and knockdown of MDR1 expression both disrupted adriamycin-induced Anxa2 phosphorylation. Interestingly, P-gp was further demonstrated to interact with Src, a tyrosine kinase upstream of Anxa2. Taken together, our results indicate that P-gp may promote the invasion of MDR breast cancer cells by modulating the tyrosine phosphorylation of Anxa2. The interaction between Anxa2 and P-gp is possibly, at least in part, responsible for the association between MDR and invasive potential in breast cancer cells.