CXCR4/SDF-1 axis mediates multidrug resistance of breast cancer

Abstract

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Multidrug resistance (MDR) and metastasis are two important properties of cancer progression. MDR phenotype in highly migratory tumor cells often becomes enhanced at metastasis sites. Once cancer cells have spread and formed secondary masses, they are largely incurable due to their enhanced MDR. MDR has been frequently associated with elevated expression of one or more ATP binding cassette transporters such as MDR-1, MRP-1, and BCRP. However, the regulation of these transporters remains controversial. CXC chemokine receptor 4 (CXCR4) has been shown to be involved in the metastasis of breast cancer and plays an important role in cancer progression. Because metastatic breast cancer remains a generally incurable and fatal disease due to the development of MDR, preventing MDR is a critical problem that needs to be addressed. In this study, we investigated whether CXCR4 is involved in the MDR of breast cancer. We measured expression levels of CXCR4 and MDR-related genes in MDR cells and compared to those in drug sensitive cells. The effect of CXCR4 on expression of MDR-related genes was evaluated. In addition, we assessed whether silencing of CXCR4 with siRNA or blocking CXCR4 interaction with stromal derived factor 1 (SDF-1) using a CXCR4 antagonist downregulates expression of MDR-related genes and increase drug sensitivity in vitro and in vivo. Our study demonstrates that CXCR4/SDF-1 axis may mediate multidrug resistance of breast cancer. The results of this study greatly enhance current understanding of chemoresistance mechanisms as it relates to management of metastatic breast cancer in the clinic. Our findings suggest that CXCR4 antagonists may themselves be potential drugs to prevent and reverse MDR.