Development of precision medicine approaches based on inter-individual variability of BCRP/ ABCG2

Abstract

Precision medicine is a rapidly-developing modality of medicine in human healthcare. Based on each patient׳s unique characteristics, more accurate dosages and drug selection can be made to achieve better therapeutic efficacy and less adverse reactions in precision medicine. A patient׳s individual parameters that affect drug transporter action can be used to develop a precision medicine guidance, due to the fact that therapeutic efficacy and adverse reactions of drugs can both be affected by expression and function of drug transporters on the cell membrane surface. The purpose of this review is to summarize unique characteristics of human breast cancer resistant protein (BCRP) and the genetic variability in the BCRP encoded gene ABCG2 in the development of precision medicine. Inter-individual variability of BCRP/ABCG2 can impact choices and outcomes of drug treatment for several diseases, including cancer chemotherapy. Several factors have been implicated in expression and function of BCRP, including genetic, epigenetic, physiologic, pathologic, and environmental factors. Understanding the roles of these factors in controlling expression and function of BCRP is critical for the development of precision medicine based on BCRP-mediated drug transport.

Keywords: 3′-UTR, 3′-untranslated region; 5-aza-C, 5-aza-2′-deoxycytidine; ABCG2, ATP-binding cassette subfamily G member 2; ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; AUC, area under curve; BCRP; BCRP, breast cancer resistant protein; Epigenetics; FTC, fumitremorgin C; Gene polymorphisms; H3K4me3, histone H3 lysine 4 trimethylation; H3K9me3, histone H3 lysine 9 trimethylation; H3S10P, histone H3 serine 10 phosphorylation; HDAC, histone deacetylase; HIF-1α, hypoxia inducible factor 1 subunit alpha; HIV-1, human immunodeficiency virus type-1; HMG-CoA, β-hydroxy-β-methyl-glutaryl-coenzyme A; MDR, multidrug resistance; MDR1, multidrug resistance 1; NBD, nucleotide binding domain; P-gp, P-glycoprotein; Physiologic factors; Precision medicine; RISC, RNA-induced silencing complex; SNP, Single nucleotide polymorphism; TKI, tyrosine kinase inhibitor; Tat, transactivator protein; miRNA, microRNA; siRNA, small RNA interference.

Graphical abstract

Figure 1

Tissue distribution of human BCRP. BCRP is highly expressed in several sites in human, including small intestine, liver, kidney, the blood–brain barrier, and placenta. The primary function of BCRP is to pump substrates from the intracellular space to the extracellular space.

Figure 2

Structure of the ABCG2 gene and BCRP protein. (A) Chromosomal location and composition of the ABCG2 gene. Locations of the 10 SNPs are indicated on the cDNA sequence. Allele frequencies of rs2231137 and rs2231142 in a global population of the 1000 Genome Project samples are indicated. ALL: 2,504 individuals in 26 groups; AFR: Africans from 5 groups; AMR: Native Americans from 6 groups; EUR: Europeans from 5 groups; SAS: South Asians from 5 groups; and EAS: East Asians from 5 groups. (B) “Half transporter” structure of BCRP protein containing six membrane-spanning domains (MSDs) and a nucleotide binding domain (NBD). Relative locations of ten SNPs are indicated on the DNA and amino acid sequences.

Figure 3

Structure of the BCRP “half-transporter” homodimer and the MDR1 “full-transporter”.

Figure 4

A strategy for the development of a precision medicine approach based on genetic polymorphisms in the ABCG2 gene in a mixed population.

Figure 5

A strategy for the development of a precision medicine approach based on DNA methylation in the ABCG2 promoter in a mixed population.

Figure 6

A strategy for the development of a precision medicine approach based on histone acetylation in the ABCG2 gene in a mixed population.

Figure 7

A strategy for the development of a precision medicine approach based on miRNA binding in the BCRP mRNA 3′-UTR in a mixed population.