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Down-regulation of microRNA-200c is associated with drug resistance in human breast cancer

Medical Oncology volume 29, pages 2527–2534 (2012)Cite this article

Abstract

Drug resistance remains a major clinical obstacle to successful treatment in breast cancer patients, and the evidence of microRNAs involvement in cancer drug resistance has been emerging recently. However, the role of microRNA-200c (miR-200c) in modulating chemoresistance of breast cancer remains largely unexplored. Here, we investigated the miR-200c expression in tumor specimens obtained from thirty-nine breast cancer patients who received neoadjuvent chemotherapy by quantitative real-time PCR. Down-regulated miR-200c was observed in non-responders as compared to responders. In addition, miR-200c expression was observed to be down-regulated over 800-fold in human breast cancer cells resistant to doxorubicin MCF-7/ADR as compared to the parental MCF-7 cells. Up-regulation of miR-200c with transfection of miR-200c mimics in breast cancer cells could enhance the chemosensitivity to epirubicin and reduce expression of multidrug resistance 1 mRNA and P-glycoprotein. Moreover, our study demonstrated that restoration of miR-200c in MCF-7/ADR cells could increase intracellular doxorubicin accumulation determined by flow cytometry. Taken together, our findings suggest that miR-200c may act as a promising therapeutic target for improvement of responsiveness to chemotherapy in breast cancer.

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References

  1. Ng EK, Wong CL, Ma ES, Kwong A. MicroRNAs as new players for diagnosis, prognosis, and therapeutic targets in breast cancer. J Oncol. 2009;2009:305420.

    PubMed  Article  Google Scholar 

  2. Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA. 2004;101(9):2999–3004.

    PubMed  Article  CAS  Google Scholar 

  3. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–97.

    PubMed  Article  CAS  Google Scholar 

  4. Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature. 2005;433(7027):769–73.

    PubMed  Article  CAS  Google Scholar 

  5. Si ML, Zhu S, Wu H, Lu Z, Wu F, Mo YY. Mir-21-mediated tumor growth. Oncogene. 2007;26(19):2799–803.

    PubMed  Article  CAS  Google Scholar 

  6. Kastl L, Brown I, Schofield AC. Mirna-34a is associated with docetaxel resistance in human breast cancer cells. Breast Cancer Res Treat. 2011.

  7. Akao Y, Noguchi S, Iio A, Kojima K, Takagi T, Naoe T. Dysregulation of microRNA-34a expression causes drug-resistance to 5-fu in human colon cancer dld-1 cells. Cancer Lett. 2011;300(2):197–204.

    PubMed  Article  CAS  Google Scholar 

  8. Miller TE, Ghoshal K, Ramaswamy B, Roy S, Datta J, et al. MicroRNA-221/222 confers tamoxifen resistance in breast cancer by targeting p27kip1. J Biol Chem. 2008;283(44):29897–903.

    PubMed  Article  CAS  Google Scholar 

  9. O’Driscoll L, Clynes M. Biomarkers and multiple drug resistance in breast cancer. Curr Cancer Drug Targets. 2006;6(5):365–84.

    PubMed  Article  Google Scholar 

  10. Takara K, Sakaeda T, Okumura K. An update on overcoming mdr1-mediated multidrug resistance in cancer chemotherapy. Curr Pharm Des. 2006;12(3):273–86.

    PubMed  Article  CAS  Google Scholar 

  11. Adam L, Zhong M, Choi W, Qi W, Nicoloso M, et al. Mir-200 expression regulates epithelial-to-mesenchymal transition in bladder cancer cells and reverses resistance to epidermal growth factor receptor therapy. Clin Cancer Res. 2009;15(16):5060–72.

    PubMed  Article  CAS  Google Scholar 

  12. Ceppi P, Mudduluru G, Kumarswamy R, Rapa I, Scagliotti GV, et al. Loss of mir-200c expression induces an aggressive, invasive, and chemoresistant phenotype in non-small cell lung cancer. Mol Cancer Res. 2010;8(9):1207–16.

    PubMed  Article  CAS  Google Scholar 

  13. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, et al. New guidelines to evaluate the response to treatment in solid tumors. European organization for research and treatment of cancer, national cancer institute of the United States, national cancer institute of Canada. J Natl Cancer Inst. 2000;92(3):205–16.

    PubMed  Article  CAS  Google Scholar 

  14. Paik JH, Jang JY, Jeon YK, Kim WY, Kim TM, et al. MicroRNA-146a downregulates nfkappab activity via targeting traf6 and functions as a tumor suppressor having strong prognostic implications in nk/t cell lymphoma. Clin Cancer Res. 2011;17(14):4761–71.

    PubMed  Article  CAS  Google Scholar 

  15. Chintamani JPS, Mittal MK, Saxena S, Bansal A, et al. Role of p-glycoprotein expression in predicting response to neoadjuvant chemotherapy in breast cancer—a prospective clinical study. World J Surg Oncol. 2005;3:61.

    PubMed  Article  CAS  Google Scholar 

  16. Yan LX, Huang XF, Shao Q, Huang MY, Deng L, et al. MicroRNA mir-21 overexpression in human breast cancer is associated with advanced clinical stage, lymph node metastasis and patient poor prognosis. Rna. 2008;14(11):2348–60.

    PubMed  Article  CAS  Google Scholar 

  17. Xu D, Lu Q, Hu X. Down-regulation of p-glycoprotein expression in mdr breast cancer cell mcf-7/adr by honokiol. Cancer Lett. 2006;243(2):274–80.

    PubMed  Article  CAS  Google Scholar 

  18. Zhu H, Wu H, Liu X, Evans BR, Medina DJ, et al. Role of microRNA mir-27a and mir-451 in the regulation of mdr1/p-glycoprotein expression in human cancer cells. Biochem Pharmacol. 2008;76(5):582–8.

    PubMed  Article  CAS  Google Scholar 

  19. Chen J, Lu L, Feng Y, Wang H, Dai L, et al. Pkd2 mediates multi-drug resistance in breast cancer cells through modulation of p-glycoprotein expression. Cancer Lett. 2011;300(1):48–56.

    PubMed  Article  CAS  Google Scholar 

  20. Kent OA, Mendell JT. A small piece in the cancer puzzle: micrornas as tumor suppressors and oncogenes. Oncogene. 2006;25(46):6188–96.

    PubMed  Article  CAS  Google Scholar 

  21. Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005;120(1):15–20.

    PubMed  Article  CAS  Google Scholar 

  22. Korpal M, Lee ES, Hu G, Kang Y. The mir-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of e-cadherin transcriptional repressors zeb1 and zeb2. J Biol Chem. 2008;283(22):14910–4.

    PubMed  Article  CAS  Google Scholar 

  23. Xia H, Ng SS, Jiang S, Cheung WK, Sze J, et al. Mir-200a-mediated downregulation of zeb2 and ctnnb1 differentially inhibits nasopharyngeal carcinoma cell growth, migration and invasion. Biochem Biophys Res Commun. 2010;391(1):535–41.

    PubMed  Article  CAS  Google Scholar 

  24. Leskela S, Leandro-Garcia LJ, Mendiola M, Barriuso J, Inglada-Perez L, et al. The mir-200 family controls beta-tubulin iii expression and is associated with paclitaxel-based treatment response and progression-free survival in ovarian cancer patients. Endocr Relat Cancer. 2011;18(1):85–95.

    PubMed  Article  CAS  Google Scholar 

  25. Gottesman MM, Ling V. The molecular basis of multidrug resistance in cancer: the early years of p-glycoprotein research. FEBS Lett. 2006;580(4):998–1009.

    PubMed  Article  CAS  Google Scholar 

  26. Kovalchuk O, Filkowski J, Meservy J, Ilnytskyy Y, Tryndyak VP, et al. Involvement of microRNA-451 in resistance of the mcf-7 breast cancer cells to chemotherapeutic drug doxorubicin. Mol Cancer Ther. 2008;7(7):2152–9.

    PubMed  Article  CAS  Google Scholar 

  27. Zheng T, Wang J, Chen X, Liu L. Role of microrna in anticancer drug resistance. Int J Cancer. 2010;126(1):2–10.

    PubMed  Article  CAS  Google Scholar 

  28. Cochrane DR, Howe EN, Spoelstra NS, Richer JK. Loss of mir-200c: a marker of aggressiveness and chemoresistance in female reproductive cancers. J Oncol. 2010;2010:821717.

    PubMed  Article  Google Scholar 

  29. Tryndyak VP, Beland FA, Pogribny IP. E-cadherin transcriptional down-regulation by epigenetic and microrna-200 family alterations is related to mesenchymal and drug-resistant phenotypes in human breast cancer cells. Int J Cancer. 2010;126(11):2575–83.

    PubMed  CAS  Google Scholar 

  30. Li Y, VandenBoom TN, Kong D, Wang Z, Ali S, et al. Up-regulation of mir-200 and let-7 by natural agents leads to the reversal of epithelial-to-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells. Cancer Res. 2009;69(16):6704–12.

    PubMed  Article  CAS  Google Scholar 

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Affiliations

  1. Department of Surgical Oncology, Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, The Second Affiliated Hospital, School of Medicine Zhejiang University, 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China

    Junqing Chen & Yongchuan Deng

  2. Department of Surgical Oncology, The Second Affiliated Hospital, School of Medicine Zhejiang University, 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China

    Wei Tian, Hongke Cai & Haifei He

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  1. Junqing Chen
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  2. Wei Tian
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  3. Hongke Cai
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  4. Haifei He
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  5. Yongchuan Deng
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Correspondence to Yongchuan Deng.

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Chen, J., Tian, W., Cai, H. et al. Down-regulation of microRNA-200c is associated with drug resistance in human breast cancer. Med Oncol 29, 2527–2534 (2012). https://doi.org/10.1007/s12032-011-0117-4

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  • DOI: https://doi.org/10.1007/s12032-011-0117-4

Keywords

  • MicroRNA
  • Breast cancer
  • Drug resistance
  • Chemotherapy
  • P-glycoprotein