**1. Introduction**

The ABCG2 protein (also named breast cancer resistance protein—BCRP, or mitoxantrone resistance protein—MXR) is a member of the ABC (ATP-binding cassette) protein superfamily. A distinguishing hallmark of ABC proteins is the presence of Walker A, Walker B, and the so-called ABC signature (typically LSGGQ) motifs in their sequences. The members of this large protein family are present in all living organisms, ranging from prokaryotes through fungi, plants, invertebrates to vertebrates. The design of ATP-binding fold and its connection to transport mechanisms seem evolutionarily beneficial, as they have been conserved through evolution [1]. In the human genome, there are 48 genes encoding ABC proteins, which are classified into seven subfamilies (denoted from A to G) primarily on the basis of sequence homology. Since an increasing number of structural and functional data are available for ABC proteins, a new classification based on these parameters has recently been proposed [2]. Most of the human ABC proteins are membrane proteins mediating translocation of substances across biological membranes using the energy of ATP binding and hydrolysis. There are some peculiar members of the family, like the regulatory ABC proteins, exemplified by the sulfonylurea receptors (SUR1/ABCC8 and SUR2/ABCC9), which control the function of other membrane proteins; or the cystic fibrosis transmembrane regulator (CFTR/ABCC7), which is an ion channel facilitating downhill chloride transport across the membrane.

Some human ABC proteins are specialized in the transport of one or a limited number of substrates. For example, MDR3/ABCB4 mediates phosphatidylcholine transport in the canalicular membrane of hepatocytes. In contrast, MDR1 (P-glycoprotein, ABCB1) is rather promiscuous, transporting a large variety of unrelated molecules. Membrane transporter proteins with broad substrate recognition may confer resistance in cells to multiple drugs, i.e., causing cross-resistance in tumor cells. These transporters are called

**Citation:** Homolya, L. Medically Important Alterations in Transport Function and Trafficking of ABCG2. *Int. J. Mol. Sci.* **2021**, *22*, 2786. https://doi.org/10.3390/ijms 22062786

Academic Editor: Thomas Falguières

Received: 9 February 2021 Accepted: 5 March 2021 Published: 10 March 2021

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**Copyright:** © 2021 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

multidrug resistance (MDR) proteins, although they also play a pivotal role at important physiological tissue barriers controlling the uptake and excretion of endo- and xenobiotics. In humans, there are multidrug transporters from the ABCB, the ABCC, and the ABCG subfamilies. These MDR proteins with their broad and partially overlapping substrate recognition, as well as with their tissue- and cell type-specific expression constitute a complex physiological network, called the chemoimmunity system, which is an essential part of the innate defense system against harmful substances [3].

ABCG2 was originally identified as a multidrug transporter in multidrug-resistant cancer cell lines, in which none of the two MDR proteins known at that time (MDR1/ABCB1 and MRP1/ABCC1) was expressed [4,5]. In drug-selected cells and certain tumors, ABCG2 is massively overexpressed and may contribute to the poor clinical outcome of these tumors [6,7]. Its physiological presence in normal tissues has also been demonstrated—first in placenta [8], and subsequently in a large variety of other tissues. The wide-ranging but still specific tissue distribution, combined with the broad substrate recognition, makes ABCG2 an essential element of the chemoimmunity network. This paper will provide an overview of the current knowledge of the structure and function of the ABCG2 protein, as well as on the medical conditions when the transporter improperly operates. A special focus will be put on the naturally occurring mutations and polymorphisms in ABCG2, which cause diminished transport activity and/or impaired cellular routing. Finally, the various methods assessing the function and trafficking of ABCG2, as well as the different efforts to rescue detrimental phenotypes caused by the faulty transporter will be discussed.
