In this study, we aimed to evaluate the relationship between PXR and ABCG2 gene expression patterns induced by proinflammatory cytokines in MCF7 and MCF7/MX breast carcinoma cell lines. The effects of proinflammatory cytokines on ABCG2 and PXR mRNA expression were studied using the real-time polymerase chain reaction method. Significant inductions in the ABCG2 and PXR mRNA levels were observed in MCF7 cells, upon treatment with interleukin-1β and tumor necrosis factor-α, whereas MCF7/MX cells did not significantly respond to the treatment. The results also show that in comparison to MCF7 cell line the basal mRNA expression level of PXR was higher in the MCF7/MX cell line. In conclusion, interleukin-1β and tumor necrosis factor-α induced ABCG2 and PXR mRNAs in the MCF7 breast cancer cell line; no significant changes on expression of the same genes in MCF7/MX cells were observed. This differential effect of the cytokines on two different cell lines seems to be influenced by basal levels of the mRNAs, which are very high in MCF7/MX cells. Similar patterns of induction in PXR and ABCG2 genes suggest a probable relationship between these two factors.
Get full access to this article
View all access options for this article.
References
1.
AlbermannN., Schmitz-WinnenthalF.H., Z'GraggenK., VolkC., HoffmannM.M., HaefeliW.E., WeissJ.2005. Expression of the drug transporters MDR1/ABCB1, MRP1/ABCC1, MRP2/ABCC2, BCRP/ABCG2, and PXR in peripheral blood mononuclear cells and their relationship with the expression in intestine and liver. Biochem Pharmacol, 70:949–958.
2.
AnapolskyA., TengS., DixitS., Piquette-MillerM.2006. The role of pregnane X receptor in 2-acetylaminofluorene-mediated induction of drug transport and -metabolizing enzymes in mice. Drug Metab Dispos, 34:405–409.
3.
BuchholzS., KellerG., SchallyA.V., HalmosG., HohlaF., HeinrichE., KoesterF., BakerB., EngelJ.B.2006. Therapy of ovarian cancers with targeted cytotoxic analogs of bombesin, somatostatin, and luteinizing hormone-releasing hormone and their combinations. Proc Natl Acad Sci, 103:10403–10407.
ChisakiI., KobayashiM., ItagakiS., HiranoT., IsekiK.2009. Liver X receptor regulates expression of MRP2 but not that of MDR1 and BCRP in the liver. Biochim Biophys Acta, 1788:2396–2403.
6.
ChoiH.K., YangJ.W., SangH.R., ChangY.H., KeonW.K.2007. Induction of multidrug resistance associated protein 2 in tamoxifen-resistant breast cancer cells. Endocr Relat Cancer, 14:293–303.
7.
di MasiA., MarinisE.D., AscenziP., MarinoM.2009. Nuclear receptors CAR and PXR: molecular, functional, and biomedical aspects. Mol Aspects Med, 30:297–343.
8.
DinarelloC.A.2006. The paradox of pro-inflammatory cytokines in cancer. Cancer Metastasis Rev, 25:307–313.
9.
DingX.W., WuJ.H., JiangC.P.2009. ABCG2: a potential marker of stem cells and novel target in stem cell and cancer therapy. Life Sci, 86:631–637.
10.
FussB., BeckerT., ZinkeI., HochM.2006. The cytohesin Steppke is essential for insulin signalling in Drosophila. Nature, 444:945–948.
11.
GerbodM.C., LiY., HolleboomA., HanS., HsuL.C., TabasI., TallA.R.2006. TNFÎ ± induces ABCA1 through NF-ΰB in macrophages and in phagocytes ingesting apoptotic cells. Proc Natl Acad Sci USA, 103:3112–3117.
12.
HannivoortR.A., DunningS., BorghtS.V., SchroyenB., WoudenbergJ., OakleyF., Buist-HomanM., van den HeuvelF.A.J., GeukenM., GeertsA., RoskamsT., FaberK.N., MoshageH.2008. Multidrug resistance-associated proteins are crucial for the viability of activated rat hepatic stellate cells. Hepatology, 48:624–634.
13.
HoE.A., Piquette-MillerM.2006. Regulation of multidrug resistance by pro-inflammatory cytokines. Curr Cancer Drug Targets, 6:295–311.
14.
IshikawaT.2009. The role of human ABC transporter ABCG2 (BCRP) in pharmacotherapy. Adv Drug Deliv Rev, 61:1–2.
15.
KimY.H., IshiiG., GotoK., OtaS., KubotaK., MurataY., MishimaM., SaijoN., NishiwakiY., OchiaiA.2009. Expression of breast cancer resistance protein is associated with a poor clinical outcome in patients with small-cell lung cancer. Lung Cancer, 65:105–111.
16.
KowalskiP., FarleyK.M., LageH., SchneiderE.2004. Effective knock down of very high ABCG2 expression by a hammerhead ribozyme. Anticancer Res, 24:2231–2235.
17.
KunduJ.K., SurhY.J.2008. Inflammation: gearing the journey to cancer. Mutat Res, 659:15–30.
18.
KuninakaS., YanoT., YokoyamaH., FukuyamaY., TerazakiY., UeharaT., KanematsuT., AsohH., IchinoseY.2000. Direct influences of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) on the proliferation and cell-surface antigen expression of cancer cells. Cytokine, 12:8–11.
19.
LiJ., LiZ.N., DuY.J., LiX.Q., BaoQ.L., ChenP.2009. Expression of MRP1, BCRP, LRP, and ERCC1 in advanced non-small-cell lung cancer: correlation with response to chemotherapy and survival. Clin Lung Cancer, 10:414–421.
20.
LinP., HuS.W., ChangT.H.2003. Correlation between gene expresson of aryl hydrocarbon receptor (AhR), hydrocarbon receptor nuclear translocator (Arnt), cytochromes P4501A1 (CYP1A1) and 1B1 (CYP1B1), and inducibility of CYP1A1 and CYP1B1 in human lymphocytes. Toxicol Sci, 71:20–26.
21.
MantovaniA., MarchesiF., PortaC., SicaA., AllavenaP.2007. Inflammation and cancer: breast cancer as a prototype. Breast, 16:27–33.
22.
Mensah-OsmanE.J., ThomasD.G., TabbM.M., LariosJ.M., HughesD.P., GiordanoT.J., LizynessM.L., RaeJ.M., BlumbergB., HollenbergP.F., BakerL.H.2007. Expression levels and activation of a PXR variant are directly related to drug resistance in osteosarcoma cell lines. Cancer, 109:957–965.
23.
MorganE.T., GoralskiK.B., Piquette-MillerM., RentonK.W., RobertsonG.R., ChaluvadiM.R., CharlesK.A., ClarkeS.J., KacevskaM., LiddleC., RichardsonT.A., SharmaR., SinalC.J.2008. Regulation of drug-metabolizing enzymes and transporters in infection, inflammation, and cancer. Drug Metab Dispos, 36:205–216.
24.
MorseS.M.J., ShawG., LarnerS.F.2006. Concurrent mRNA and protein extraction from the same experimental sample using a commercially available column-based RNA preparation kit. Biotechniques, 40:54–58.
25.
MosaffaF., LageH., AfshariJ.T., BehravanJ.2009. Interleukin-1 beta and tumor necrosis factor-alpha increase ABCG2 expression in MCF-7 breast carcinoma cell line and its mitoxantrone-resistant derivative, MCF-7/MX. Inflamm Res, 58:669–676.
26.
MottinoA.D., CataniaV.A.2008. Hepatic drug transporters and nuclear receptors: Regulation by therapeutic agents. World J Gastroenterol, 14:7068–7074.
27.
PollerB., DreweJ., KrahenbahlS., HuwylerJ., GutmannH.2010. Regulation of BCRP (ABCG2) and P-Glycoprotein (ABCB1) by cytokines in a model of the human blood-brain barrier. Cell Mol Neurobiol, 30:63–70.
28.
PulmbJ.A., MiloryR., KayeJ.B.1989. Effect of the pH dependence of 3-(4,5-dimethylthiazol-2- yl)–2,5–diphenyl–tetrazolium bromide formazan absorbtion on chemosensitivity determined by a novel tetrazolium-based assay. Cancer Res, 49:4435–4440.
29.
SchweitzerA., KnauerS.K., StaubertR.H.2008. Therapeutic potential of nuclear receptors. Expert Opin Ther Pat, 18:861–888.
30.
UrquhartB.L., TironaR.G., KimR.B.2007. Nuclear receptors and the regulation of drug-metabolizing enzymes and drug transporters: implications for interindividual variability in response to drugs. J Clin Pharmacol, 47:566–578.
31.
Van Der HeijdenJ., De JongM.C., DijkmansB.A.C., LemsW.F., OerlemansR., KathmannI., SchalkwijkC.G., SchefferG.L., ScheperR.J., JansenG.2004. Development of sulfasalazine resistance in human T cells induces expression of the multidrug resistance transporter ABCG2 (BCRP) and augmented production of TNF-αAnn Rheum Dis, 63:138–143.
