The breast cancer resistance protein BCRP (ABCG2) concentrates drugs and carcinogenic xenotoxins into milk

Jonker, Johan W.; Merino, Gracia; Musters, Sandra; Herwaarden, Antonius E. van; Bolscher, Ellen; Wagenaar, Els; Mesman, Elly; Dale, Trevor; Schinkel, Alfred H.

doi:10.1038/nm1186

Cited by 378 publications

(315 citation statements)

References 11 publications

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“…However, there is some controversy over how universal this association may be [29,30]. Recently, we have demonstrated that Bcrp1 is highly expressed in the apical membrane of mammary alveolar epithelial cells during late pregnancy and lactation, whereas it is not detectable in mammary epithelial cells of virgins [31]. Here we show that in virgin mice, a small number of cells in mammary ducts were found to express Bcrp1.…”

Section: Discussionmentioning

confidence: 57%

Contribution of the ABC Transporters Bcrp1 and Mdr1a/1b to the Side Population Phenotype in Mammary Gland and Bone Marrow of Mice

et al. 2005

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The ability of cells to export Hoechst 33342 can be used to identify a subpopulation of cells (side population [SP]) with characteristics of stem cells in many tissues. The ATP-binding cassette transporters Bcrp1 (Abcg2) and Mdr1a/1b (Abcb1a/1b) have been implicated as being responsible for this phenotype. To further explore the involvement of these transporters in the SP phenotype, we have generated Bcrp1/ Mdr1a/1b triple knockout mice and studied the effect of their absence on the SP in bone marrow and mammary gland.Whereas in bone marrow Bcrp1 was almost exclusively responsible for the SP, both transporters contributed to the SP phenotype in the mammary gland, where their combined absence resulted in a nearly complete loss of SP. Interestingly, bone marrow of Mdr1a/1b −/− mice frequently displayed an elevated SP, which was reversible by the Bcrp1 inhibitor Ko143, suggesting that Bcrp1 can compensate for the loss of Mdr1a/1b in bone marrow. Stem Cells 2005;23:1059-1065

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Section: Discussionmentioning

confidence: 57%

Contribution of the ABC Transporters Bcrp1 and Mdr1a/1b to the Side Population Phenotype in Mammary Gland and Bone Marrow of Mice

et al. 2005

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“…In an ATPdependent process, ABCG2 transports various xenobiotics and cytostatic drugs across the plasma membrane (Litman et al 2000). Analysis of different stages of mammary development by immunohistochemistry and Western analysis revealed that ABCG2 was not expressed in virgin mice but was greatly induced during late pregnancy and especially during lactation (Jonker et al 2005). They demonstrated that ABCG2 expression is confined to the apical membrane of alveolar, but not ductal mammary epithelial cells of mice, cows, and humans and is responsible for the active secretion of clinically and toxicologically important substrates into mouse milk.…”

Section: Discussionmentioning

confidence: 99%

“…A single nucleotide polymorphism (SNP) capable of encoding a substitution of tyrosine-581 to serine in ABCG2 is most likely responsible for the major QTL affecting milk yield and composition. Jonker et al (2005) demonstrated that ABGC2 is responsible for the active secretion of clinically and toxicologically important substrates into mouse milk, and that mice homozygous for By combining comparative genomics and in silico gene cloning, we produced a map of genes and sequence variation in the critical region of the QTL (Fig. 1).…”

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confidence: 99%

Identification of a missense mutation in the bovine ABCG2 gene with a major effect on the QTL on chromosome 6 affecting milk yield and composition in Holstein cattle

Cohen¹,

Seroussi²,

Larkin³

et al. 2005

Genome Res.

351

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We previously localized a quantitative trait locus (QTL) on chromosome 6 affecting milk fat and protein concentration to a 4-cM confidence interval, centered on the microsatellite BM143. We characterized the genes and sequence variation in this region and identified common haplotypes spanning five polymorphic sites in the genes IBSP, SPP1, PKD2, and ABCG2 for two sires heterozygous for this QTL. Expression of SPP1 and ABCG2 in the bovine mammary gland increased from parturition through lactation. SPP1 and all the coding exons of ABCG2 and PKD2 were sequenced for these two sires. The single nucleotide change capable of encoding a substitution of tyrosine-581 to serine (Y581S) in the ABCG2 transporter was the only polymorphism corresponding to the segregation status of all 3 heterozygous and 15 homozygous sires for the QTL in the Israeli and U.S. Holstein populations. The allele substitution fixed effects on the genetic evaluations of 335 Israeli sires were −341 kg milk, +0.16% fat, and +0.13% protein (F-value = 200). No other polymorphism gave significant effect for fat and protein concentration in models that also included Y581S. The allele substitution effects on the genetic evaluations of 670 cows, daughters of two heterozygous sires, were −226 kg milk, 0.09% fat, and 0.08% protein (F-value = 394), with partial dominance towards the 581S homozygotes. We therefore propose that Y581S in ABCG2 is the causative site for this QTL.

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“…The results of biodistribution and functional studies have indicated that BCRP plays important physiologic and pharmacologic roles, particularly in the clearance of toxic agents from the gastrointestinal tract, blood-brain barrier, liver, placenta, and mammary glands (22,38,39). With respect to hematologic cells, BCRP has been identified in hematopoietic stem cells (40) and dendritic cells (41).…”

mentioning

confidence: 99%

Involvement of breast cancer resistance protein expression on rheumatoid arthritis synovial tissue macrophages in resistance to methotrexate and leflunomide

Heijden¹,

Oerlemans²,

Tak³

et al. 2009

Arthritis & Rheumatism

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Objective. To determine whether multidrugresistance efflux transporters are expressed on immune effector cells in synovial tissue from patients with rheumatoid arthritis (RA) and compromise the efficacy of methotrexate (MTX) and leflunomide (LEF).Methods. Synovial tissue biopsy samples obtained from RA patients before treatment and 4 months after starting treatment with MTX (n ‫؍‬ 17) or LEF (n ‫؍‬ 13) were examined by immunohistochemical staining and digital image analysis for the expression of the drug efflux transporters P-glycoprotein, multidrug resistance-associated protein 1 (MRP-1) through MRP-5, MRP-8, MRP-9, and breast cancer resistance protein (BCRP), and the relationship to clinical efficacy of MTX and LEF was assessed.Results. BCRP expression was observed in all RA synovial biopsy samples, both pretreatment and posttreatment, but not in control noninflammatory synovial tissue samples from orthopedic patients. BCRP expression was found both in the intimal lining layer and on macrophages and endothelial cells in the synovial sublining. Total numbers of macrophages in RA patients decreased upon treatment; in biopsy samples with persistently high macrophage counts, 2-fold higher BCRP expression was observed. Furthermore, median BCRP expression was significantly increased (3-fold) in nonresponders to disease-modifying antirheumatic drugs (DMARDs) compared with responders to DMARDs (P ‫؍‬ 0.048). Low expression of MRP-1 was found on synovial macrophages, along with moderate expression in T cell areas of synovial biopsy specimens from one-third of the RA patients.Conclusion. These findings show that the drug resistance-related proteins BCRP and MRP-1 are expressed on inflammatory cells in RA synovial tissue. Since MTX is a substrate for both BCRP and MRP-1, and LEF is a high-affinity substrate for BCRP, these transporters may contribute to reduced therapeutic efficacy of these DMARDs.

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The breast cancer resistance protein BCRP (ABCG2) concentrates drugs and carcinogenic xenotoxins into milk

Cited by 378 publications

References 11 publications

Contribution of the ABC Transporters Bcrp1 and Mdr1a/1b to the Side Population Phenotype in Mammary Gland and Bone Marrow of Mice

Contribution of the ABC Transporters Bcrp1 and Mdr1a/1b to the Side Population Phenotype in Mammary Gland and Bone Marrow of Mice

Identification of a missense mutation in the bovine ABCG2 gene with a major effect on the QTL on chromosome 6 affecting milk yield and composition in Holstein cattle

Involvement of breast cancer resistance protein expression on rheumatoid arthritis synovial tissue macrophages in resistance to methotrexate and leflunomide

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