A multidrug transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci USA

Greenebaum Cancer Center of the University of Maryland, Baltimore MD 21201, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/1999; 95(26):15665-70. DOI: 10.1073/pnas.95.26.15665
Source: PubMed


MCF-7/AdrVp is a multidrug-resistant human breast cancer subline that displays an ATP-dependent reduction in the intracellular accumulation of anthracycline anticancer drugs in the absence of overexpression of known multidrug resistance transporters such as P glycoprotein or the multidrug resistance protein. RNA fingerprinting led to the identification of a 2.4-kb mRNA that is overexpressed in MCF-7/AdrVp cells relative to parental MCF-7 cells. The mRNA encodes a 655-aa [corrected] member of the ATP-binding cassette superfamily of transporters that we term breast cancer resistance protein (BCRP). Enforced expression of the full-length BCRP cDNA in MCF-7 breast cancer cells confers resistance to mitoxantrone, doxorubicin, and daunorubicin, reduces daunorubicin accumulation and retention, and causes an ATP-dependent enhancement of the efflux of rhodamine 123 in the cloned transfected cells. BCRP is a xenobiotic transporter that appears to play a major role in the multidrug resistance phenotype of MCF-7/AdrVp human breast cancer cells.

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    • "Many intrinsic and acquired properties such as overexpression of anti-apoptotic proteins, drug efflux transporters , and detoxifying enzymes make CSCs resistant to anticancer drugs [16]. ATP-binding cassette sub-family G member 2 (ABCG2) is a major multidrug resistance pump that renders cancer cells resistant to chemotherapeutic drugs [17], which is a downstream target of sonic hedgehog (SHH)-glioma-associated oncogene homolog (GLI) pathway [18]. SHH signal is critical for the tumorigenesis of primary gastric CSCs that is mediated through Patched 1 (PTCH1) and smoothened (SMO) receptors, where the absence or presence of HH ligands controls the PTCH1 and SMO activities [19]. "
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    ABSTRACT: Drug resistance in gastric cancer largely results from the gastric cancer stem cells (GCSCs), which could be targeted to improve the efficacy of chemotherapy. In this study, we identified a subpopulation of GCSCs enriched in holoclones that expressed CD44(+)/Musashi-1(+) stem cell biomarkers, capable of self-renewal and proliferation. Enriched CD44(+)/Musashi-1(+) GCSCs demonstrated elevated expression of sonic hedgehog (SHH) and glioma-associated oncogene homolog 1 (GLI1), the well-known signaling pathway molecules involving in the drug resistance. Further, CD44(+)/Musashi-1(+) cells exhibited high drug efflux bump activity and were resistant to doxorubicin (Dox)-induced apoptosis, and unregulated the ATP-binding cassette sub-family G member 2 (ABCG2) expression,. The above effects on apoptosis were reversed in the presence of GLI inhibitors, GANT61 and GDC-0449, or by the knockdown of GLI1/SHH. Upon knockdown of GLI1, expression of ABCG2 was downregulated the antitumor effects were significantly improved as observed in the gastric cancer xenograft. Collectively, our study revealed that co-expression of CD44(+)/Musashi-1(+) could be used to identify GCSCs, which also accounts for the drug resistance in gastric cancer. SHH-GLI and its downstream effector ABCG2 could be better targeted to possibly improve the efficacy of chemotherapy in drug-resistant gastric cancers. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Cancer letters 08/2015; DOI:10.1016/j.canlet.2015.08.005 · 5.62 Impact Factor
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    • "Comparison of the nucleotide sequence of TcABCG1 gene of the TcI strains with the sequence of NEsmo haplotype showed several SNPs that produced 11 amino acid changes. TcABCG1 transporter exhibits 29% similarity with the ABCG2 human transporter, also known as breast cancer resistance protein (Doyle et al. 1998). This transporter plays a role in multidrug resistance to chemotherapeutic agents. "
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    ABSTRACT: Benznidazole (BZ) is one of the two drugs used for Chagas disease treatment. Nevertheless therapeutic failures of BZ have been reported, which were mostly attributed to variable drug susceptibility among Trypanosoma cruzi strains. ATP-binding cassette (ABC) transporters are involved in a variety of translocation processes and some members have been implicated in drug resistance. Here we report the characterisation of the first T. cruzi ABCG transporter gene, named TcABCG1, which is over-expressed in parasite strains naturally resistant to BZ. Comparison of TcABCG1 gene sequence of two TcI BZ-resistant strains with CL Brener BZ-susceptible strain showed several single nucleotide polymorphisms, which determined 11 amino acid changes. CL Brener transfected with TcI transporter genes showed 40-47% increased resistance to BZ, whereas no statistical significant increment in drug resistance was observed when CL Brener was transfected with the homologous gene. Only in the parasites transfected with TcI genes there was 2-2.6-fold increased abundance of TcABCG1 transporter protein. The analysis in wild type strains also suggests that the level of TcABCG1 transporter is related to BZ natural resistance. The characteristics of untranslated regions of TcABCG1 genes of BZ-susceptible and resistant strains were investigated by computational tools.
    Memórias do Instituto Oswaldo Cruz 04/2015; 110(ahead). DOI:10.1590/0074-02760140407 · 1.59 Impact Factor
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    • "BCRP is situated in the apical membrane of epithelial cells in numerous tissues including the intestine, liver, kidneys, and several blood–tissue barriers where it serves to extrude its substrates and by these means limiting availability and systemic exposure (Jonker et al. 2000; Maliepaard et al. 2001; Zhang et al. 2004). Furthermore, BCRP is highly expressed in cancer cells where it prevents the uptake of the antineoplastic drug mitoxantrone, diminishing its therapeutic effect (Doyle et al. 1998; Bates et al. 2001). Thus, one important biological function of BCRP in most tissues appears to comprise cellular protection and detoxification. "
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    ABSTRACT: Breast cancer resistance protein (Bcrp/Abcg2) and multidrug transporter 1 (Mdr1/Abcb1) are efflux proteins located in the apical membrane of mammary epithelial cells (MEC). Bcrp is induced in MEC during gestation and lactation, while Mdr1 is down-regulated during lactation. Numerous drugs and toxic compounds are known to be actively secreted into milk by Bcrp, but most chemicals have not been investigated in this respect, emphasizing the need for functional Bcrp studies in an established cell line with secreting mammary epithelial cells. The present study was undertaken to examine expressions of Bcrp and Mdr1 in mammary epithelial HC11 cells, derived from a mid-gestational murine mammary gland. In addition, Bcrp function was assessed by transport experiments with mitoxantrone (MX) in undifferentiated HC11 cells, in HC11 cells subjected to Bcrp RNA interference (RNAi), as well as in HC11 cells stimulated to differentiate by treatment with lactogenic hormones. Differentiated HC11 cells organized into alveolar-resembling structures and gene expression of the major milk protein β-casein was induced, whereas undifferentiated cells formed monolayers with lower β-casein expression. Bcrp and Mdr1 gene and protein were expressed in both undifferentiated and differentiated HC11 cells. Differentiation of HC11 cells resulted in increased Bcrp protein expression, while Mdr1 gene and protein expressions were reduced. The Bcrp inhibitor elacridar (GF120918) reduced secretion and increased accumulation of MX in both undifferentiated and differentiated HC11 cells. Silencing of the Bcrp gene caused an increased accumulation of MX. The results indicate that the HC11 cell model provides a promising tool to investigate transport of potential Bcrp substrates in mammary epithelial cells.
    Cell Biology and Toxicology 03/2015; 31(2). DOI:10.1007/s10565-015-9298-5 · 2.68 Impact Factor
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