ABCG2: a perspective

Abstract

ABCG2, or breast cancer resistance protein (BCRP), is an ABC transporter that has been the subject of intense study since its discovery a decade ago. With high normal tissue expression in the brain endothelium, gastrointestinal tract, and placenta, ABCG2 is believed to be important in the protection from xenobiotics, regulating oral bioavailability, forming part of the blood-brain barrier, the blood-testis barrier, and the maternal-fetal barrier. Notably, ABCG2 is often expressed in stem cell populations, where it likely plays a role in xenobiotic protection. However, clues to its epigenetic regulation in various cell populations are only beginning to emerge. While ABCG2 overexpression has been demonstrated in cancer cells after in vitro drug treatment, endogenous ABCG2 expression in certain cancers is likely a reflection of the differentiated phenotype of the cell of origin and likely contributes to intrinsic drug resistance. Notably, research into the transporter's role in cancer drug resistance and its development as a therapeutic target in cancer has lagged. Substrates and inhibitors of the transporter have been described, among them chemotherapy drugs, tyrosine kinase inhibitors, antivirals, HMG-CoA reductase inhibitors, carcinogens, and flavonoids. This broad range of substrates complements the efficiency of ABCG2 as a transporter in laboratory studies and suggests that, while there are redundant mechanisms of xenobiotic protection, the protein is important in normal physiology. Indeed, emerging studies in pharmacology and toxicology assessing polymorphic variants in man, in combination with murine knockout models have confirmed its dynamic role. Work in pharmacology may eventually lead us to a greater understanding of the physiologic role of ABCG2.

Figure 1

Evolutionary analysis of ABCG2. A) Full length sequences of all full-length mammalian genes, chicken and ABCG1 were aligned used to build a phylogenetic tree using the Minimal Evolution method. Numbers represent the percent of bootstraps supporting that node. B) The domains of the ABCG2 protein are shown to scale along with the percent identity of each domain. Inter, inter-domain region; 1=TM domain and loop 1.

Figure 2

Expression of ABCG2 in normal tissues. Formalin-fixed, paraffin embedded tissue sections were stained with the polyclonal anti-ABCG2 antibody 87405. Hematoxylin and 3,3′-diaminobenzidene counterstain. Tissues shown are the adrenal gland (A), kidney (B), testis (C), placenta (D), and lung (E).

Figure 3

ABC transporter expression decreases intracellular imatinib accumulation. ABCG2-and ABCB1-transfected HEK 293 cells were incubated for 2 with 0.2 μM ¹⁴C-imatinib in the presence (balck bars) or absence (grey bars) of 10 μM FTC or 200 nM tariquidar, respectively. Inhibition of transporter activity significantly increased intracellular imatinib concentration as measured by liquid scintillation counting compared to cells incubated in the absence of inhibitor.