Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2)
Top Cited Papers
- 20 October 2003
- journal article
- review article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 22 (47), 7340-7358
- https://doi.org/10.1038/sj.onc.1206938
Abstract
Observations of functional adenosine triphosphate (ATP)-dependent drug efflux in certain multidrug-resistant cancer cell lines without overexpression of P-glycoprotein or multidrug resistance protein (MRP) family members suggested the existence of another ATP-binding cassette (ABC) transporter capable of causing cancer drug resistance. In one such cell line (MCF-7/AdrVp), the overexpression of a novel member of the G subfamily of ABC transporters was found. The new transporter was termed the breast cancer resistance protein (BCRP), because of its identification in MCF-7 human breast carcinoma cells. BCRP is a 655 amino-acid polypeptide, formally designated as ABCG2. Like all members of the ABC G (white) subfamily, BCRP is a half transporter. Transfection and enforced overexpression of BCRP in drug-sensitive MCF-7 or MDA-MB-231 cells recapitulates the drug-resistance phenotype of MCF-7/AdrVp cells, consistent with current evidence suggesting that functional BCRP is a homodimer. BCRP maps to chromosome 4q22, downstream from a TATA-less promoter. The spectrum of anticancer drugs effluxed by BCRP includes mitoxantrone, camptothecin-derived and indolocarbazole topoisomerase I inhibitors, methotrexate, flavopiridol, and quinazoline ErbB1 inhibitors. Transport of anthracyclines is variable and appears to depend on the presence of a BCRP mutation at codon 482. Potent and specific inhibitors of BCRP are now being developed, opening the door to clinical applications of BCRP inhibition. Owing to tissue localization in the placenta, bile canaliculi, colon, small bowel, and brain microvessel endothelium, BCRP may play a role in protecting the organism from potentially harmful xenobiotics. BCRP expression has also been demonstrated in pluripotential 'side population' stem cells, responsible for the characteristic ability of these cells to exclude Hoechst 33342 dye, and possibly for the maintenance of the stem cell phenotype. Studies are emerging on the role of BCRP expression in drug resistance in clinical cancers. More prospective studies are needed, preferably combining BCRP protein or mRNA quantification with functional assays, in order to determine the contribution of BCRP to drug resistance in human cancers.This publication has 79 references indexed in Scilit:
- Liver and marrow of adult mdr-1a/1b−/− mice show normal generation, function, and multi-tissue trafficking of primitive hematopoietic cellsExperimental Hematology, 2002
- A new multidrug resistance protein at the blood–brain barrierBiochemical and Biophysical Research Communications, 2002
- Nestin-positive progenitor cells derived from adult human pancreatic islets of Langerhans contain side population (SP) cells defined by expression of the ABCG2 (BCRP1) ATP-binding cassette transporterBiochemical and Biophysical Research Communications, 2002
- Estrone and 17β‐Estradiol Reverse Breast Cancer Resistance Protein‐mediated Multidrug ResistanceJapanese Journal of Cancer Research, 2002
- Transport of 7-Ethyl-10-hydroxycamptothecin (SN-38) by Breast Cancer Resistance Protein ABCG2 in Human Lung Cancer CellsBiochemical and Biophysical Research Communications, 2001
- Functional Characterization of the Human Multidrug Transporter, ABCG2, Expressed in Insect CellsBiochemical and Biophysical Research Communications, 2001
- Expression of Multidrug Resistance-related Transporters in Human Breast CarcinomaJapanese Journal of Cancer Research, 2001
- Selection and characterization of a high-activity ribozyme directed against the antineoplastic drug resistance–associated ABC transporter BCRP/MXR/ABCG2Cancer Gene Therapy, 2001
- Breast Cancer Resistance Protein Directly Confers SN-38 Resistance of Lung Cancer CellsBiochemical and Biophysical Research Communications, 2001
- The Product of the ABC Half-Transporter Gene ABCG2 (BCRP/MXR/ABCP) Is Expressed in the Plasma MembraneBiochemical and Biophysical Research Communications, 2000