Elsevier

Biochemical Pharmacology

Volume 83, Issue 8, 15 April 2012, Pages 1084-1103
Biochemical Pharmacology

Review
Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance

https://doi.org/10.1016/j.bcp.2012.01.002Get rights and content

Abstract

Since cloning of the ATP-binding cassette (ABC) family member breast cancer resistance protein (BCRP/ABCG2) and its characterization as a multidrug resistance efflux transporter in 1998, BCRP has been the subject of more than two thousand scholarly articles. In normal tissues, BCRP functions as a defense mechanism against toxins and xenobiotics, with expression in the gut, bile canaliculi, placenta, blood-testis and blood-brain barriers facilitating excretion and limiting absorption of potentially toxic substrate molecules, including many cancer chemotherapeutic drugs. BCRP also plays a key role in heme and folate homeostasis, which may help normal cells survive under conditions of hypoxia. BCRP expression appears to be a characteristic of certain normal tissue stem cells termed “side population cells,” which are identified on flow cytometric analysis by their ability to exclude Hoechst 33342, a BCRP substrate fluorescent dye. Hence, BCRP expression may contribute to the natural resistance and longevity of these normal stem cells. Malignant tissues can exploit the properties of BCRP to survive hypoxia and to evade exposure to chemotherapeutic drugs. Evidence is mounting that many cancers display subpopulations of stem cells that are responsible for tumor self-renewal. Such stem cells frequently manifest the “side population” phenotype characterized by expression of BCRP and other ABC transporters. Along with other factors, these transporters may contribute to the inherent resistance of these neoplasms and their failure to be cured.

Introduction

The influence of ATP-binding cassette (ABC) transporters – and breast cancer resistance protein (BCRP, ABCG2) in particular – on resistance of human cancers to antineoplastic pharmaceuticals should be viewed as the combined effects of the role that the transporter plays in normal tissues to affect drug absorption, distribution, metabolism and excretion (ADME), and the effects of the expression of the transporter in neoplastic tissues to produce active efflux of chemotherapeutic molecules. A review of the literature on this subject through the year 2008 was published by our group in 2010 [1]; the present paper will update findings on this topic since 2008, but does not include an extensive listing of the many drugs that are substrates or inhibitors of BCRP/ABCG2; such listings can be found in other recent reviews of BCRP/ABCG2 [2], [3], [4], [5], [6], [7], [8], [9].

Section snippets

History and nomenclature

In the 1970s multidrug resistance emerged as a significant cellular mechanism to explain/account for the clinical resistance of cancer cells to standard cancer chemotherapeutic agents. Initially P-glycoprotein (Pgp/ABCB1) and later multidrug resistance protein (MRP1/ABCC1) were identified as drug efflux proteins contributing to the multidrug resistance phenotype. However, in a subset of leukemia cells from patients, the transport activity of these two proteins could not account entirely for the

Summary of findings through 2008 [1]

BCRP expression in normal tissues can affect the ADME of antineoplastic drugs. For example BCRP expression in the intestine or liver (bile canaliculi) can affect absorption and elimination of BCRP substrate drugs; BCRP expression in the BBB or BTB can affect penetration of drugs transported by BCRP as well. The expression and function of endogenous BCRP can be affected by SNPs of the gene. The most frequently observed non-synonymous SNPs in the BCRP coding region occur in exon 2 (G34A,

Hematologic and lymphoid malignancies

BCRP has the potential to play an important role in drug resistance in hematologic malignancies, as it is frequently expressed on malignant hematopoietic and lymphoid cells, and some of the drugs used to treat these cancers are BCRP substrates. Additionally, BCRP is expressed on stem cells in leukemias, potentially contributing to their resistance to eradication by chemotherapy or targeted therapies. Finally, an evolving literature associates BCRP SNPs not only with treatment response, but with

Summary of findings through 2008 [1]

As with the hematologic malignancies, our last review found data emerging in solid tumors associating BCRP expression with adverse outcomes. At that time, it was not known whether the adverse outcome caused by BCRP expression was directly related to resistance mediated by the efflux function of BCRP or whether BCRP expression served as a marker for the presence of other mediators of poor-risk cancers such as activity of signaling pathways controlling cellular proliferation, self-renewal,

Final discussion

The past three years have seen significant strides in elucidating the role of BCRP in cancer drug resistance. It is clear that BCRP exerts a negative effect on cancer treatment outcomes both at the level of the neoplastic cell itself and by virtue of its effects on anticancer drug ADME in the host.

Data are starting to accumulate defining the role that common polymorphisms of BCRP play in the toxicity of antineoplastic drugs and treatment outcome; although some studies found enhanced drug

Acknowledgement

Funded by a VA Merit Review Grant (to Dr. Ross), a Leukemia and Lymphoma Society Translational Research Award and by University of Maryland, Baltimore UMMG Cancer Research Grant #CH 649 CRF issued by the State of Maryland Department of Health and Mental Hygiene (DHMH) under the Cigarette Restitution Fund Program (to Dr Baer), and by NCI Cancer Center Support Grant P30 CA134274.

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