Roles of Multidrug Resistance Genes in Breast Cancer Chemoresistance

  • M. Tien Kuo
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 608)


ATP binding cassette (ABC)-containing drug efflux transporters play important roles in regulating intracellular drug concentrations that determine cell sensitivity to chemotherapeutic agents. Of particular relevance to cancer chemotherapy are the transporters P-glycoprotein (Pgp) encoded by multidrug resistance 1 gene, multidrug resistance protein (MRP), and breast cancer resistance protein (BCRP). More than 80% of currently used antitumor agents can be transported by these three transporters, and overexpression of these transporters renders multidrug resistance to a broad spectrum of antitumor agents. Elevated expression of these transporters is frequently found in breast cancers and correlations with elevated expression of Pgp or MRP1 to chemotherapeutic outcomes have been observed in some cases, suggesting that these transporters may contribute to chemoresistance in breast cancers. However, attempts to modulate the activities of these transporters using reversal agents have met with limited success. Future studies should focus on better understanding of the upregulation mechanisms of ABC transporter genes in breast cancers, and of the pharmacologic mechanisms of transporter-reversal agent interactions. These studies may lead to novel strategies for improving chemotherapeutic efficacies through targeted interventions of these ABC transporters.


Breast Cancer Multidrug Resistance Breast Cancer Resistance Protein Multidrug Resistance Protein Reversal Agent 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Bray F, McCarron P, Parkin DM. The changing global patterns of female breast cancer incidence and mortality. Breast Cancer Res 2004; 6:229–239.CrossRefPubMedGoogle Scholar
  2. 2.
    Jemal A, Tiwari RC, Murray T et al. Cancer statistics, 2004. CA cancer J Clin 2004; 54:8–29.CrossRefPubMedGoogle Scholar
  3. 3.
    Giordano SH, Buzdar AU, Smith TL et al. Is breast cancer survival improving? Cancer 2004; 100:44–52.CrossRefPubMedGoogle Scholar
  4. 4.
    Hortobagyi GN. Treatment of breast cancer. N Engl J Med 1998; 339:974–984.CrossRefPubMedGoogle Scholar
  5. 5.
    Piccart M. The roles of taxenes in the adjuvant treatment of early breast cancers. Breast Cancer Res Treat 2003; 79:S25–S34.CrossRefPubMedGoogle Scholar
  6. 6.
    Nabholtz JMA. Docetaxel-an thracycline combinations in metastatic brease cancers. Breast Cancer Res Treat 2003; 79:S3–S9.CrossRefPubMedGoogle Scholar
  7. 7.
    Valero V, Holmes FA, Walters RS et al. Phase II trial of docetaxel: A new, highly effective antineoplastic agent in the management of patients with anthracycline-resistant metastatic breast cancer. J Clin Oncol 1995; 13:23886–2894.Google Scholar
  8. 8.
    Nabholtz JM, Gelmon K, Bontenbal M et al. Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer. J Clin Onco 1996; 14:1858–1867.Google Scholar
  9. 9.
    Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biophys Acta Biochim 1975; 445:152–162.Google Scholar
  10. 10.
    Cole SP, Bhardway JH, Gerlach JE et al. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 1992; 258:1650–1654.CrossRefPubMedGoogle Scholar
  11. 11.
    Doyle LA, Yang W, Abruzzo LV et al. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci USA 1998; 5:15665–15670.CrossRefGoogle Scholar
  12. 12.
    Deng L, Tatebe S, Lin-Lee YC et al. MDR and MRP gene families as cellular determinant factors for resistance to clinical anticancer agents. Cancer Treat Res 2002; 112:49–66.PubMedGoogle Scholar
  13. 13.
    Schinkel AH, Jonker JW. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: An overview. Adv Drug Deliv Rev 2003; 55:3–29.CrossRefPubMedGoogle Scholar
  14. 14.
    Borst P, Elferink RO. Mammalian ABC transporters in health and disease. Annu Rev Biochem 2002; 71:537–592.CrossRefPubMedGoogle Scholar
  15. 15.
    Chang G, Roth CB. Structure of MsbA from E. coli: A homolog of the multidrug resistance ATP binding cassette (ABC) transporters. Science 2001; 293:1793–1800.CrossRefPubMedGoogle Scholar
  16. 16.
    Higgins CF, Linton KJ. The ATP switch model for ABC transporter. Nature Struct Mol Biol 2004; 11:918–926.CrossRefGoogle Scholar
  17. 17.
    Schinkel AH, Smit JJM, Van Tellingen O et al. Disruption of the mouse mdrla P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 1994; 77:491–502.CrossRefPubMedGoogle Scholar
  18. 18.
    Schinkel AH, Mayer U, Wagenaar E et al. Normal viability and altered pharmacokinetics in mice lacking mdrl-type (drug-transporting) P-glycoproteins. Proc Natl Acad Sci USA 1997; 94:4028–4033.CrossRefPubMedGoogle Scholar
  19. 19.
    Scotto KW. Transcriptional regulation of ABC drug transporters. Oncogene 2003; 22:7496–7511.CrossRefPubMedGoogle Scholar
  20. 20.
    Kuo MT, Liu Z, Wei Y et al. Induction of human MDR1 gene expression by 2-acetylaminofluorene is mediated by effectors of the phosphoinositide 3-kinase pathway that activate NF-kappaB signaling. Oncogene 2002; 21:1945–1954.CrossRefPubMedGoogle Scholar
  21. 21.
    Zhan M, Yu D, Lin J et al. Transcriptional repression of protein kinase Cα via Sp1 by wild-type p53 is involved in inhibition of MDR1 P-glycoprotein phosphorylation. J Biol Chem 2005; 280:4825–4833.CrossRefPubMedGoogle Scholar
  22. 22.
    Bakos E, Evers R, Szakacs G et al. Functional multidrug resistance protein (MRP1) lacking the N-terminal transmembrane domain. J Biol Chem 1998; 273:32167–32175.CrossRefPubMedGoogle Scholar
  23. 23.
    Kruh GD, Belinsky MG. The MRP family of drug efflux pumps. Oncogene 2003; 22:7537–7552.CrossRefPubMedGoogle Scholar
  24. 24.
    Heimeur A, Conseil G, Deeley RG et al. The MRP-related and BCRP/ABCG2 multidrug resistance proteins: Biology, substrate specificity and regulation. Curr Drug Metab 2004; 5:21–53.CrossRefGoogle Scholar
  25. 25.
    Wijnholds J, Evers R, van Leusden MR et al. Increased sensitivity to anticancer drugs and decreased inflammatory response in mice lacking the multidrug resistance-associated protein. Nature Med 1997; 3:1275–1279.CrossRefPubMedGoogle Scholar
  26. 26.
    Keppler D, Kartenbeck J. The canalicular conjugate export pump encoded by the cmrp/cmoat gene. Prog Liver Dis 1996; 14:55–67.PubMedGoogle Scholar
  27. 27.
    Zelcer N, Saeki T, Reid G et al. Characterization of drug transport by the human mulltidrug resistance protein 3 (ABCC3). J Biol Chem 2001; 276:46400–46407.CrossRefPubMedGoogle Scholar
  28. 28.
    Schuetz JD, Connelly MC, Sun D et al. MRP4: A previously unidentified factor in resistance to nucleoside-based antiviral drugs. Naure Med 1999; 5:1048–1051.CrossRefGoogle Scholar
  29. 29.
    Yamane Y, Furuichi M, Song R et al. Expression of multidrug resistance protein/GS-X pump and gamma-glutamylcysteine synthetase genes is regulated by oxidative stress. J Biol Chem 1998; 273:31075–31085.CrossRefPubMedGoogle Scholar
  30. 30.
    Kuo MT, Bao JJ, Curley SA et al. Frequent coordinated overexpression of the MRP/GS-X pump and gamma-glutamylcysteine synthetase genes in human colorectal cancers. Cancer Res 1996; 56:3642–3644.PubMedGoogle Scholar
  31. 31.
    Zipper LM, Mulcahy RT. The Keap1 BTB/POZ dimerization function is required to sequester Nrf2 in cytoplasm. J Biol Chem 2002; 277:36544–36552.CrossRefPubMedGoogle Scholar
  32. 32.
    Lin-Lee YC, Tatebe S, Savaraj N et al. Differential sensitivities of the MRP gene family and gamma-glutamylcysteine synthetase to prooxidants in human colorectal carcinoma cell lines with different p53 status. Biochem Pharmacol 2001; 61:555–563.CrossRefPubMedGoogle Scholar
  33. 33.
    Allen JD, Schinkel AH. Multidrug resistance and pharmacological protein mediated by the breast cancer resistance protein (BCRP/ABCG2). Mol Cancer Therap 2002; 1:427–434.Google Scholar
  34. 34.
    Doyle LA, Ross DD. Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2). Oncogene 2003; 22:7340–7358.CrossRefPubMedGoogle Scholar
  35. 35.
    Bates SE, Robey R, Miyake K et al. The roles of half-transporters in multidrug resistance. J Bioenergetics and Biomem 2001; 33:503–517.CrossRefGoogle Scholar
  36. 36.
    Jonker JW, Buitelaar M, Wagenaar E et al. The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria. Proc Natl Acad Sci USA 2002; 99:15649–15654.CrossRefPubMedGoogle Scholar
  37. 37.
    Leonessa F, Clarke R. ATP binding cassette transporters and drug resistance in brease cancer. Endocrine-related Cancer 2003; 10:43–73.CrossRefPubMedGoogle Scholar
  38. 38.
    Beck WT, Grogan TM, Willman CL et al. Methods to detect P-glycoprotein-associated multidrug resistance in patients’ tumors: Consensus recommendations. Cancer Res 1996; 56:3010–3020.PubMedGoogle Scholar
  39. 39.
    Verrelle P, Meissonnier F, Fonck Y et al. Clinical relevance of immunohistochemical detection of multidrug resistance P-glycoprotein in breast carcinoma. J Nat Cancer Inst 1991; 83:111–116.CrossRefPubMedGoogle Scholar
  40. 40.
    Chevillard S, Pouillart P, Beldjord C et al. Sequential assessment of multidrug resistance phenotype and measurement of S-phase fraction as predictive markers of breast cancer response to neoadjuvant chemotherapy. Cancer 1996; 77:292–300.CrossRefPubMedGoogle Scholar
  41. 41.
    Rudas M, Filipits M, Taucher S et al. Expression of MRP1, LRP and Pgp in breast carcinoma patients treated with preoperative chemotherapy. Breast Cancer Res Treat 2003; 81:149–157.CrossRefPubMedGoogle Scholar
  42. 42.
    Filipits M, Malayeri R, Suchomel RW et al. Expression of the multidrug resistance protein (MRP1) in breast cancer. Anticancer Res 1999; 19:5043–5049.PubMedGoogle Scholar
  43. 43.
    Ferrero JM, Etienne MC, Formento JL et al. Application of an original RT-PCR-ELISA multiplex assay for MDR1 and MRP, along with p53 determination in node-positive breast cancer patients. Br J Cancer 2000; 82:171–177.CrossRefPubMedGoogle Scholar
  44. 44.
    Faneyte IF, Kristel PM, van de Vijver MJ. Multidurg resistance associated genes MRP1, MRP2 and MRP3 in primary and anthracycline exposed breast cancer. Anticancer Res 2004; 24:2931–2939.PubMedGoogle Scholar
  45. 45.
    Kanzaki A, Toi M, Nakayama K et al. Expression of multidrug resistance-related transporters in human breast carcinoma. Jpn J Cancer Res 2001; 92:452–458.PubMedGoogle Scholar
  46. 46.
    Van den Heuvel-Eibrink MM, Wiemer EA, Prins A et al. Leukemia. 2002; 16:833–839.CrossRefPubMedGoogle Scholar
  47. 47.
    Sargent JM, Williamson CJ, Maliepaard M et al. Breast cancer resistance protein expression and resistance to daunorubicin in blast cells from patients with acute myeloid leukaemia. Brit J Haematol 2001; 115:257–262.CrossRefGoogle Scholar
  48. 48.
    Faneyte IF, Kristel PM, Maliepaard M et al. Expression of the breast cancer resistance protein in breast cancer. Clinic Cancer Res 2002; 8:1068–1074.Google Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2007

Authors and Affiliations

  • M. Tien Kuo
    • 1
  1. 1.Department of Molecular Pathology, Unit 89The University of Texas M.D. Anderson Cancer CenterHoustonUSA

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