A multidrug resistance transporter from human MCF-7 breast cancer cells

Abstract

MCF-7/AdrVp is a multidrug-resistant human breast cancer subline that displays an ATP-dependent reduction in the intracellular accumulation of anthracycline anticancer drugs in the absence of overexpression of known multidrug resistance transporters such as P glycoprotein or the multidrug resistance protein. RNA fingerprinting led to the identification of a 2.4-kb mRNA that is overexpressed in MCF-7/AdrVp cells relative to parental MCF-7 cells. The mRNA encodes a 663-aa member of the ATP-binding cassette superfamily of transporters that we term breast cancer resistance protein (BCRP). Enforced expression of the full-length BCRP cDNA in MCF-7 breast cancer cells confers resistance to mitoxantrone, doxorubicin, and daunorubicin, reduces daunorubicin accumulation and retention, and causes an ATP-dependent enhancement of the efflux of rhodamine 123 in the cloned transfected cells. BCRP is a xenobiotic transporter that appears to play a major role in the multidrug resistance phenotype of MCF-7/AdrVp human breast cancer cells.

Identification of genes that confer tumor cell resistance to the Aurora B kinase inhibitor, AZD1152

“…Although it was originally identified as a drug resistance gene by several laboratories, [26][27][28][29] it is still unclear how significant a role it plays in clinical drug resistance. Though amplification of the ABCG2 gene has been observed during the selection of drug-resistant cell lines.…”

Drug transporters: recent advances concerning BCRP and tyrosine kinase inhibitors

“…Breast cancer resistance protein is a half transporter member of the ABCG subfamily (ABCG2) and was first identified by Doyle et al (1998) in a human breast cancer cell line selected for doxorubicin resistance in the presence of verapamil, an inhibitor of P-gp. Overexpression of BCRP is associated with resistance to a wide range of different anticancer agents including mitoxantrone, camptothecins, anthracyclines, flavopiridol and antifolates (Table 1) (Assaraf, 2006;Robey et al, 2007).…”

Both P-gp and MRP2 mediate transport of Lopinavir, a protease inhibitor

“…The expression of a BCRP homologue, known as brain multidrug resistance protein (BMRP), has also been reported in porcine brain capillary endothelial cells (Eisenblatter et al, 2003). Both BCRP and BMRP possess one half of the MDR1 P-gp structure with only six transmembrane domains and one ATP binding domain (Doyle et al, 1998). In addition to this structural similarity, most known substrates for BCRP/BMRP are similar to P-gp (i.e., hydrophobic, amphiphilic xenobiotics), suggesting that PIs may also interact with BCRP/BMRP Doyle and Ross, 2003).…”