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MDR1 (C3435T) polymorphism: relation to the risk of breast cancer and therapeutic outcome

The Pharmacogenomics Journal volume 10, pages 62–69 (2010)Cite this article

Abstract

P-glycoprotein (PGP), the product of the MDR1 gene, is a transmembrane active efflux pump for a variety of carcinogens and cytostatics. It has been suggested that MDR1 polymorphisms contribute to the variability in cancer risk and therapeutic outcome. We examined the relevance of C3435T polymorphism in relation to breast cancer susceptibility, clinical and pathological characteristics of breast carcinoma, the therapeutic response and hematologic toxicities after anthracycline-based chemotherapy. A significant association between allele frequencies and histological type, stage and histological grade was observed (P=0.024, 0.014, 0.006, respectively, χ2-test or Fisher's exact test). We also found significantly higher (P=0.019, χ2-test) T allele frequency in breast cancer patients (n=221) than in controls (n=113). A significantly enhanced therapeutic outcome after neoadjuvant therapy (n=38; P=0.021, Fisher's exact test) and longer time to progression after anthracycline-based chemotherapy (n=102; P=0.049, log-rank test) were observed in CC homozygotes. However, no significant association between hematologic toxicities and C3435T polymorphism was detectable.

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References

  1. Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P . Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 2007; 18: 581–592.

    Article  CAS  PubMed  Google Scholar 

  2. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T et al. Cancer statistics, 2008. CA Cancer J Clin 2008; 58: 71–96.

    Article  PubMed  Google Scholar 

  3. Lester J . Breast cancer in 2007: incidence, risk assessment, and risk reduction strategies. Clin J Oncol Nurs 2007; 11: 619–622.

    Article  PubMed  Google Scholar 

  4. Fossland VS, Stroop JB, Schwartz RC, Kurtzman SH . Genetic issues in patients with breast cancer. Surg Oncol Clin N Am 2009; 18: 53–71.

    Article  PubMed  Google Scholar 

  5. Stearns V, Davidson NE, Flockhart DA . Pharmacogenetics in the treatment of breast cancer. Pharmacogenomics J 2004; 4: 143–153.

    Article  CAS  PubMed  Google Scholar 

  6. Robert J, Le Morvan V, Smith D, Pourquier P, Bonnet J . Predicting drug response and toxicity based on gene polymorphisms. Crit Rev Oncol Hematol 2005; 54: 171–196.

    Article  PubMed  Google Scholar 

  7. Zhou SF . Structure, function and regulation of p-glycoprotein and its clinical relevance in drug disposition. Xenobiotica 2008; 38: 802–832.

    Article  CAS  PubMed  Google Scholar 

  8. Leslie EM, Deeley RG, Cole SP . Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol Appl Pharmacol 2005; 204: 216–237.

    Article  CAS  PubMed  Google Scholar 

  9. Kerb R . Implications of genetic polymorphisms in drug transporters for pharmacotherapy. Cancer Lett 2006; 234: 4–33.

    Article  CAS  PubMed  Google Scholar 

  10. Fromm MF . The influence of MDR1 polymorphisms on p-glycoprotein expression and function in humans. Adv Drug Deliv Rev 2002; 54: 1295–1310.

    Article  CAS  PubMed  Google Scholar 

  11. Leonessa F, Clarke R . ATP binding cassette transporters and drug resistance in breast cancer. Endocr Relat Cancer 2003; 10: 43–73.

    Article  CAS  PubMed  Google Scholar 

  12. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 2000; 97: 3473–3478.

    Article  CAS  PubMed  Google Scholar 

  13. Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV et al. A ‘silent’ polymorphism in the MDR1 gene changes substrate specificity. Science 2007; 315: 525–528.

    Article  CAS  Google Scholar 

  14. Siegsmund M, Brinkmann U, Scháffeler E, Weirich G, Schwab M, Eichelbaum M et al. Association of the p-glycoprotein transporter MDR1C3435T polymorphism with the susceptibility to renal epithelial tumors. J Am Soc Nephrol 2002; 13: 1847–1854.

    Article  CAS  PubMed  Google Scholar 

  15. Leschziner GD, Andrew T, Pirmohamed M, Johnson MR . ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research. Pharmacogenomics J 2007; 7: 154–179.

    Article  CAS  PubMed  Google Scholar 

  16. Ferguson LR, De Flora S . Multiple drug resistance, antimutagenesis and anticarcinogenesis. Mutat Res 2005; 591: 24–33.

    Article  CAS  PubMed  Google Scholar 

  17. Zhou SF . Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica 2008; 38: 802–832.

    Article  CAS  PubMed  Google Scholar 

  18. Kurzawski M, DroŸdzik M, Suchy J, Kurzawski G, Białecka M, Górnik W . Polymorphism in the p-glycoprotein drug transporter MDR1 gene in colon cancer patients. Eur J Clin Pharmacol 2005; 61: 389–394.

    Article  CAS  PubMed  Google Scholar 

  19. Jamroziak K, Mlynarski W, Balcerczak E, Mistygacz M, Trelinska J, Mirowski M et al. Functional C3435T polymorphism of MDR1 gene: an impact on genetic susceptibility and clinical outcome of childhood acute lymphoblastic leukemia. Eur J Haematol 2004; 72: 314–321.

    Article  CAS  PubMed  Google Scholar 

  20. Illmer T, Schuler US, Thiede C, Schwarz UI, Kim RB, Gotthard S et al. MDR1 gene polymorphisms affect therapy outcome in acute myeloid leukemia patients. Cancer Res 2002; 62: 4955–4962.

    CAS  PubMed  Google Scholar 

  21. DeBruin LS, Josephy PD . Perspectives on the chemical etiology of breast cancer. Environ Health Perspect 2002; 110: 119–128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Turgut S, Yaren A, Kursunluoglu R, Turgut G . MDR1 C3435T polymorphism in patients with breast cancer. Arch Med Res 2007; 38: 539–544.

    Article  CAS  PubMed  Google Scholar 

  23. Tatari F, Salek R, Mosaffa F, Khedri A, Behravan J . Association of C3435T single-nucleotide polymorphism of MDR1 gene with breast cancer in an Iranian population. DNA Cell Biol 2009; 28: 259–263.

    Article  CAS  PubMed  Google Scholar 

  24. Gervasini G, Carrillo JA, Garcia M, San JC, Cabanillas A, Benitez J . Adenosine triphosphate-binding cassette B1 (ABCB1) (multidrug resistance 1) G2677T=A gene polymorphism is associated with high risk of lung cancer. Cancer 2006; 107: 2850–2857.

    Article  CAS  PubMed  Google Scholar 

  25. Stanulla M, Schäffeler E, Arens S, Rathmann A, Scharauder A, Welte K et al. GSTP1 and MDR1 genotypes and central nervous system relapse in childhood acute lymphoblastic leukemia. Int J Hemato 2005; 81: 39–44.

    Article  CAS  Google Scholar 

  26. Miller KL, Kelsey KT, Wiencke JK, Moghadassi M, Miike R, Liu M et al. The C3435T polymorphism of MDR1 and susceptibility to adult glioma. Neuroepidemiology 2005; 25: 85–90.

    Article  PubMed  Google Scholar 

  27. Gerlach JH, Kartner N, Bell DR, Ling V . Multidrug resistance. Cancer Surv 1986; 5: 25–46.

    CAS  PubMed  Google Scholar 

  28. Kafka A, Sauer G, Jaeger C, Grundmann R, Kreienberg R, Zeillinger R et al. Polymorphism C3435T of the MDR-1 gene predicts response to preoperative chemotherapy in locally advanced breast cancer. Int J Oncol 2003; 22: 1117–1121.

    CAS  PubMed  Google Scholar 

  29. Rodrigues FFO, Santos RE, Melo MB, Silva MALG, Oliveira AL, Rozenowicz RL et al. Correlation of polymorphism C3435T of the MDR-1 gene and the response of primary chemotherapy in women with locally advanced breast cancer. Genet Mol Res 2008; 7: 177–183.

    Article  CAS  PubMed  Google Scholar 

  30. Klimecki WT, Futscher BW, Grogan TM, Dalton WS . P-glycoprotein expression and function in circulating blood cells from normal volunteers. Blood 1994; 83: 2451–2458.

    CAS  PubMed  Google Scholar 

  31. Oselin K, Nowakowski-Gashaw I, Mrozikiewicz PM, Wolbergs D, Pahkla R, Roots I . Quantitative determination of MDR1 mRNA expression in peripheral blood lymphocytes: a possible role of genetic polymorphisms in the MDR1 gene. Eur J Clin Invest 2003; 33: 261–267.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the reviewers for their constructive reviews and helpful comments. This research project was supported by the Ministry of Health of the Slovak Republic (grant No. 2005/46-VOUKE-01) and by the Slovak Grant Agency for Science (VEGA grant No. 1/2282/05 and 1/3372/06).

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine, P. J. Safarik University, Kosice, Slovak Republic

    M Cizmarikova, L Schonova, A Kohut, A Linkova, M Sarissky, J Mojzis, L Mirossay & A Mirossay

  2. Department of Radiotherapy and Oncology, East Oncology Institute, Kosice, Slovak Republic

    M Wagnerova

  3. Department of Medical Biology, Faculty of Medicine, P. J. Safarik University, Kosice, Slovak Republic

    V Habalova

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  1. M Cizmarikova
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Correspondence to A Mirossay.

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Cizmarikova, M., Wagnerova, M., Schonova, L. et al. MDR1 (C3435T) polymorphism: relation to the risk of breast cancer and therapeutic outcome. Pharmacogenomics J 10, 62–69 (2010). https://doi.org/10.1038/tpj.2009.41

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