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.

Lipid Regulation of the ABCB1 and ABCG2 Multidrug Transporters

“…Professional lipid ABC transporters, such as the cholesterol and phospholipid transporter ABCA1, the long-chain PC and cholesterol transporter ABCB4 (MDR3), the bile salt transporter ABCB11 (BSEP/S-P-gp), or the major sterol transporters ABCG5/G8 (working as an obligate heterodimer), have indeed been shown to be regulated by lipid-sensing NRs (Beyea et al, 2007;Jonker et al, 2009;Schmitz & Langmann, 2005;Tarling et al, 2013;van Meer et al, 2008). Interestingly, to date, several NRs also involved in the recognition of lipid ligands have been shown to affect the gene expression of human ABCB1 and ABCG2, the transport functions of which are mainly involved in causing multidrug resistance (Borst & Elferink, 2002;Jonker et al, 2009;Klaassen & Aleksunes, 2010;Natarajan, Xie, Baer, & Ross, 2012;Sarkadi et al, 2006;Scotto, 2003). Therefore, via binding to and activating their cognate NRs, lipid molecules might also be directly involved in the transcriptional regulation of both ABCB1 and ABCG2.…”

BCRP Expression in VX2 Rabbit Liver Tumours and its Effects on Tumour Recurrence, Metastasis and Treatment Tolerability

“…The high expression of BCRP in tumor cells could specifically transport mitoxantrone, methotrexate, camptothecin and many anticancer drugs, forming the important cause of tumor cell resistance (Robey et al, 2009;Ni et al, 2010;Getz et al, 2011). Recent researched suggested that BCRP had protective effects on stem cell differentiation and development, and would have a large number expression in cancer stem cells Ding et al, 2010;Natarajan et al, 2012), which might provide the theoretical support of BCRP's potential overcoming the tumor resistance.…”

“…Cai-Xia Li*, Kai Zhang, Fu-Bo Xie in cancer stem cells Ding et al, 2010;Natarajan et al, 2012), which might provide the theoretical support of BCRP's potential overcoming the tumor resistance.…”

Molecular mechanisms of drug resistance and its reversal in cancer

“…In contrast to Pgp and MRP1, it contains only one NBD preceding one TMD with six membrane spanning helices (Ni et al, 2010). BCRP has been identified to have a potential impact on drug resistance in hematologic malignancies like AML and CML due to its frequent expression on malignant hematopoietic and lymphoid cells (Natarajan et al, 2012). Although several BCRP substrates are transported out of the cell at low concentrations, they are also inhibitors of BCRP at higher concentrations.…”