Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance

Abstract

Since cloning of the ATP-binding cassette (ABC) family member breast cancer resistance protein (BCRP/ABCG2) and its characterization as a multidrug resistance efflux transporter in 1998, BCRP has been the subject of more than two thousand scholarly articles. In normal tissues, BCRP functions as a defense mechanism against toxins and xenobiotics, with expression in the gut, bile canaliculi, placenta, blood-testis and blood-brain barriers facilitating excretion and limiting absorption of potentially toxic substrate molecules, including many cancer chemotherapeutic drugs. BCRP also plays a key role in heme and folate homeostasis, which may help normal cells survive under conditions of hypoxia. BCRP expression appears to be a characteristic of certain normal tissue stem cells termed "side population cells," which are identified on flow cytometric analysis by their ability to exclude Hoechst 33342, a BCRP substrate fluorescent dye. Hence, BCRP expression may contribute to the natural resistance and longevity of these normal stem cells. Malignant tissues can exploit the properties of BCRP to survive hypoxia and to evade exposure to chemotherapeutic drugs. Evidence is mounting that many cancers display subpopulations of stem cells that are responsible for tumor self-renewal. Such stem cells frequently manifest the "side population" phenotype characterized by expression of BCRP and other ABC transporters. Along with other factors, these transporters may contribute to the inherent resistance of these neoplasms and their failure to be cured.

Figure 1

Schematic of the physical properties of BCRP. BCRP is translated in the ER as a nonfunctional monomer consisting of one NBD and six TMDs. After proper protein folding and glycosylation of asparagine 596 in the ER, BCRP is transported through the Golgi to the plasma membrane where it localizes as a functional oligomer comprised of four homodimers joined by disulfide linkages involving cysteine 603. The exact site and sequence of homodimerization and oligomerization of BCRP is still unclear. Subsequent to its function, oligomeric BCRP is degraded in the lysosome. Any misfolded BCRP is recognized early on in the ER and is targeted to the proteasome for degradation.

Figure 2

Schematic representation of transcriptional regulation of BCRP expression. Transcription factors that bind to cis elements upstream of the BCRP E1B/C promoter with subsequent activation or repression of the promoter are depicted diagrammatically. Signaling pathways and extracellular stimuli that stimulate binding of the transcription factors are also shown. The position of the various experimentally verified BCRP cis regulatory elements in relation to the transcription start site of the BCRP E1B/C first exon are also shown. The trans and cis regulatory elements were compiled from the literature cited in Section 2e, “Regulation of BCRP expression and function” of this review.