The effect of ABCB1 polymorphisms on the outcome of breast cancer treatment

Abstract

The ABCB1 gene encodes a permeability glycoprotein, which is one of the most extensively studied human adenosine-triphosphate (ATP)-dependent efflux transporters. Permeability glycoprotein is expressed in the apical membranes of tissues such as intestine, liver, blood-brain barrier, kidney, placenta, and testis and contributes to intracellular drug disposition. It is also highly expressed in tumor cells conferring drug resistance, which is one of the major problems in the efficacy of cancer chemotherapy treatment. ABCB1 is highly polymorphic, and three well-known single-nucleotide polymorphisms such as 1236C>T, 2677G>T/A, and 3435C>T have been found to be associated with altered messenger RNA levels, protein folding, and drug pharmacokinetics. Many association studies and meta-analyses have demonstrated the clinical impact of ABCB1 polymorphisms in breast cancer treatment outcomes with respect to therapeutic response, chemotoxicity, and overall survival. Therefore, the aim of this review was to evaluate the effects of ABCB1 polymorphisms on the outcome of breast cancer treatment which, in future, would be important for tailoring individualized anticancer therapy.

Keywords: ABCB1; P-glycoprotein; breast cancer treatment; chemotherapy; drug resistance; polymorphisms; response.

Figure 1

A. Molecular structure of ABCB1 gene: Containing 28 exons and 28 introns; encoding P-gp of 1280 amino acids. B. Secondary structure of P-gp protein: This has a single polypeptide chain with both the N and C termini located inside the cytoplasmic region while the 12 trans-membrane domains are located inside the plasma membrane. It also consists of two nucleotide binding domains (NBD), which act as ATP binding sites. The first extracellular loop contains three glycosylation sites. Abbreviations: mRNA, messenger RNA; NBD, nucleotide-binding domain.