Observations of functional
adenosine triphosphate (
ATP)-dependent drug efflux in certain multidrug-resistant
cancer cell lines without overexpression of
P-glycoprotein or multidrug resistance
protein (MRP) family members suggested the existence of another
ATP-binding cassette (
ABC) transporter capable of causing
cancer drug resistance. In one such cell line (MCF-7/AdrVp), the overexpression of a novel member of the G subfamily of
ABC transporters was found. The new transporter was termed the
breast cancer resistance
protein (BCRP), because of its identification in MCF-7 human
breast carcinoma cells. BCRP is a 655
amino-acid polypeptide, formally designated as ABCG2. Like all members of the ABC G (white) subfamily, BCRP is a half transporter. Transfection and enforced overexpression of BCRP in drug-sensitive MCF-7 or MDA-MB-231 cells recapitulates the drug-resistance phenotype of MCF-7/AdrVp cells, consistent with current evidence suggesting that functional BCRP is a homodimer. BCRP maps to chromosome 4q22, downstream from a TATA-less promoter. The spectrum of anticancer drugs effluxed by BCRP includes
mitoxantrone,
camptothecin-derived and indolocarbazole
topoisomerase I inhibitors,
methotrexate,
flavopiridol, and
quinazoline ErbB1 inhibitors. Transport of
anthracyclines is variable and appears to depend on the presence of a BCRP mutation at
codon 482. Potent and specific inhibitors of BCRP are now being developed, opening the door to clinical applications of BCRP inhibition. Owing to tissue localization in the placenta, bile canaliculi, colon, small bowel, and brain microvessel endothelium, BCRP may play a role in protecting the organism from potentially harmful
xenobiotics. BCRP expression has also been demonstrated in pluripotential "side population" stem cells, responsible for the characteristic ability of these cells to exclude
Hoechst 33342 dye, and possibly for the maintenance of the stem cell phenotype. Studies are emerging on the role of BCRP expression in drug resistance in clinical
cancers. More prospective studies are needed, preferably combining BCRP
protein or
mRNA quantification with functional assays, in order to determine the contribution of BCRP to drug resistance in human
cancers.