Multidrug resistance in breast cancer: from in vitro models to clinical studies

Abstract

The development of multidrug resistance (MDR) and subsequent relapse on therapy is a widespread problem in breast cancer, but our understanding of the underlying molecular mechanisms is incomplete. Numerous studies have aimed to establish the role of drug transporter pumps in MDR and to link their expression to response to chemotherapy. The ATP-binding cassette (ABC) transporters are central to breast cancer MDR, and increases in ABC expression levels have been shown to correlate with decreases in response to various chemotherapy drugs and a reduction in overall survival. But as there is a large degree of redundancy between different ABC transporters, this correlation has not been seen in all studies. This paper provides an introduction to the key molecules associated with breast cancer MDR and summarises evidence of their potential roles reported from model systems and clinical studies. We provide possible explanations for why despite several decades of research, the precise role of ABC transporters in breast cancer MDR remains elusive.

Figure 1

(a). An example of the general structure an ABC transporter with 2 sets of transmembrane domains (TMD) and 2 nucleotide binding domains (NBD). Substrate molecules are present in the inner membrane shown in orange. Upon binding of ATP, the NBD become joined, leading to a conformational change (b). This change causes the movement of the substrate out of the membrane.

Figure 2

Structure of P-glycoprotein (PGP)—this ABC transporter consists of 12 transmembrane domains and 2 ATP binding sites. Other transporters with a similar structure include MDR4, MRP4, MRP5 and MRP7.

Figure 3

Structure of Multidrug Resistance Protein 1 (MRP1)—this ABC transporter is similar in structure to PGP in that they possess 2 ATP binding sites. In addition to the 12 transmembrane domains, they also contain an additional 5 transmembrane domains at the amino terminal end. Other transporters with a similar structure include MRP2, MRP3 and MRP6.

Figure 4

Structure of Breast Cancer Resistance Protein (BCRP)—this ABC transporter contains 6 transmembrane domain and 1 ATP binding site on the amino terminal side of the transmembrane domain. This is known as a “half transporter,” these are thought to form dimmers in order to function.