Role of ABCB5 P-Glycoprotein in Breast Cancer Multidrug Resistance.

摘要

Multidrug resistance mediated by P-glycoprotein and related ATP- binding cassette (ABC) transporters is an impediment to successful cancer therapy. Here we have examined for the first time the expression of the novel ABCB5 transporter in human physiological mammary gland tissue and in a panel of human breast cancer cell lines in an initial effort to characterize whether ABCB5 might contribute to breast cancer chemoresistance. We found ABCB5 mRNA highly expressed not only in human skin and malignant melanoma tumors but also in physiological human mammary gland tissue and in MDA-MB-435 and MDA-N, but not BT-549 MCF-7 or T-47D breast cancer cell lines. Correlation analysis between ABCB5 gene expression across 20 human cancer cell lines of the NCI-60 panel with the growth inhibitory potencies of 119 standard anticancer drugs with known mechanisms of action revealed significant negative correlations for 45 of the 119 drugs considered pointing to a possible function of ABCB5 as a MDR transporter of broad specificity. The role of ABCB5 as a cancer chemoresistance mediator was experimentally validated for one of the negatively correlated agents (doxorubicin) in ABCB5-expressing melanoma cells and our results showed that ABCB5 confers doxorubicin resistance via its function as a doxorubicin efflux transporter. Our results demonstrate for the first time ABCB5 P- glycoprotein gene expression in mammary gland tissue and in a subset of breastcancer cell lines indicating that ABCB5 may contribute to breast cancer chemoresistance in expressing tumors.