Effect of the breast-cancer resistance protein on atypical multidrug resistance

Abstract

Simultaneous resistance of malignant cells to several antineoplastic agents that are structurally and functionally unrelated is known as multidrug resistance. It is one of the main causes of chemotherapy failure. Besides the classic multidrug-resistant phenotype, mediated by increased activity of the ATP-binding cassette (ABC) transporter P-glycoprotein, there are other multidrug-resistant tumours, with resistance caused by different mechanisms. This is called atypical multidrug resistance. Pronounced overexpression of a novel ABC transporter has been observed in various human cancer cell lines with atypical multidrug resistance (which were established by in vitro exposure to mitoxantrone, topotecan, doxorubicin, or bisantrene). This novel transporter was originally named breast-cancer resistance protein (BCRP). BCRP is a 655-aminoacid protein of about 72 kDa. It can be thought of as an ABC 'half-transporter', and it forms dimers to produce an active transport complex. Transfection experiments with BCRP cDNA showed that the phenotype of atypical multidrug resistance could be transferred to formerly drug-sensitive cancer cells. Although the role of BCRP in drug resistance of clinical cancers is still unclear, preliminary data obtained by mRNA and protein expression analyses support the assumption that it has a role in clinical multidrug resistance.