Breast Cancer Research and Treatment

, Volume 139, Issue 3, pp 717–730 | Cite as

MiR-181a enhances drug sensitivity in mitoxantone-resistant breast cancer cells by targeting breast cancer resistance protein (BCRP/ABCG2)

  • Xuyang Jiao
  • Lin Zhao
  • Mengtao Ma
  • Xuefeng Bai
  • Miao He
  • Yuanyuan Yan
  • Yan Wang
  • Qiuchen Chen
  • Xinnan Zhao
  • Mingyi Zhou
  • Zeshi Cui
  • Zhihong Zheng
  • Enhua Wang
  • Minjie Wei
Preclinical Study

Abstract

Breast cancer resistance protein (BCRP)/ATP-binding cassette subfamily G member 2 (ABCG2) mediates multidrug resistance (MDR) in breast cancers. In this study, we aimed to investigate the role of microRNAs in regulation of BCRP expression and BCRP-mediated drug resistance in breast cancer cells. Microarray analysis was performed to determine the differential expression patterns of miRNAs that target BCRP between the MX-resistant breast cancer cell line MCF-7/MX and its parental MX-sensitive cell line MCF-7. MiR-181a was found to be the most significantly down-regulated miRNA in MCF-7/MX cells. Luciferase activity assay showed that miR-181a mimics inhibited BCRP expression by targeting the 3′ untranslated region (UTR) of the BCRP mRNA. Overexpression of miR-181a down-regulated BCRP expression, and sensitized MX-resistant MCF-7/MX cells to MX. In a nude mouse xenograft model, intratumoral injection of miR-181a mimics inhibited BCRP expression, and enhanced the antitumor activity of MX. In addition, miR-181a inhibitors up-regulated BCRP expression, and rendered MX-sensitive MCF-7 cells resistant to MX. These findings suggest that miR-181a regulates BCRP expression via binding to the 3′-UTR of BCRP mRNA. MiR-181a is critical for regulation of BCRP-mediated resistance to MX. MiR-181a may be a potential target for preventing and reversing drug resistance in breast cancer.

Keywords

MicroRNA-181a BCRP Drug resistance Breast cancer 

Notes

Acknowledgments

We are grateful to Dr Zhirong Zhan (Molecular Therapeutics Section, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA) for providing the MCF-7/MX cell. We also greatly appreciate the generous help from Qinghuan Xiao for typing and editing this manuscript. This work was supported by grants from National Natural Science Foundation of China (No. 30973559, No. 81173092), and this study was also supported by Liaoning S&T Projects (No. 2011415052), and Shenyang Technology Projects (No. F11-264-1-19).

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1.
    Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002, CA. Cancer J Clin 55(2):74–108CrossRefGoogle Scholar
  2. 2.
    Kuo MT (2007) Roles of multidrug resistance genes in breast cancer chemoresistance. Adv Exp Med Biol 608:23–30PubMedCrossRefGoogle Scholar
  3. 3.
    Knutsen T, Rao VK, Ried T, Mickley L, Schneider E, Miyake K, Ghadimi BM, Padilla-Nash H, Pack S, Greenberger L, Cowan K, Dean M, Fojo T, Bates S (2000) Amplification of 4q21–q22 and the MXR gene in independently derived mitoxantrone-resistant cell lines. Genes Chromosomes Cancer 27(1):110–116PubMedCrossRefGoogle Scholar
  4. 4.
    Ni Z, Bikadi Z, Rosenberg MF, Mao Q (2010) Structure and function of the human breast cancer resistance protein (BCRP/ABCG2). Curr Drug Metab 11(7):603–617PubMedCrossRefGoogle Scholar
  5. 5.
    Nakanishi T, Ross DD (2012) Breast cancer resistance protein (BCRP/ABCG2): its role in multidrug resistance and regulation of its gene expression. Chin J Cancer 31(2):73–99. doi:10.5732/cjc.011.10320 PubMedCrossRefGoogle Scholar
  6. 6.
    Shiozawa K, Oka M, Soda H, Yoshikawa M, Ikegami Y, Tsurutani J, Nakatomi K, Nakamura Y, Doi S, Kitazaki T, Mizuta Y, Murase K, Yoshida H, Ross DD, Kohno S (2004) Reversal of breast cancer resistance protein (BCRP/ABCG2)-mediated drug resistance by novobiocin, a coumermycin antibiotic. Int J Cancer 108(1):146–151. doi:10.1002/ijc.11528 PubMedCrossRefGoogle Scholar
  7. 7.
    Selever J, Gu G, Lewis MT, Beyer A, Herynk MH, Covington KR, Tsimelzon A, Dontu G, Provost P, Di Pietro A, Boumendjel A, Albain K, Miele L, Weiss H, Barone I, Ando S, Fuqua SA (2011) Dicer-mediated upregulation of BCRP confers tamoxifen resistance in human breast cancer cells. Clin Cancer Res 17(20):6510–6521. doi:10.1158/1078-0432.ccr-11-1403 PubMedCrossRefGoogle Scholar
  8. 8.
    Hou X, Huang F, Carboni JM, Flatten K, Asmann YW, Ten Eyck C, Nakanishi T, Tibodeau JD, Ross DD, Gottardis MM, Erlichman C, Kaufmann SH, Haluska P (2011) Drug efflux by breast cancer resistance protein is a mechanism of resistance to the benzimidazole insulin-like growth factor receptor/insulin receptor inhibitor, BMS-536924. Mol Cancer Ther 10(1):117–125. doi:10.1158/1535-7163.mct-10-0438 PubMedCrossRefGoogle Scholar
  9. 9.
    Burger H, Foekens JA, Look MP, Meijer-van Gelder ME, Klijn JG, Wiemer EA, Stoter G, Nooter K (2003) RNA expression of breast cancer resistance protein, lung resistance-related protein, multidrug resistance-associated proteins 1 and 2, and multidrug resistance gene 1 in breast cancer: correlation with chemotherapeutic response. Clin Cancer Res 9(2):827–836PubMedGoogle Scholar
  10. 10.
    Nguyen NP, Almeida FS, Chi A, Nguyen LM, Cohen D, Karlsson U, Vinh-Hung V (2010) Molecular biology of breast cancer stem cells: potential clinical applications. Cancer Treat Rev 36(6):485–491. doi:10.1016/j.ctrv.2010.02.016 PubMedCrossRefGoogle Scholar
  11. 11.
    Fiorucci G, Chiantore MV, Mangino G, Percario ZA, Affabris E, Romeo G (2012) Cancer regulator microRNA: potential relevance in diagnosis, prognosis and treatment of cancer. Curr Med Chem 19(4):461–474PubMedCrossRefGoogle Scholar
  12. 12.
    Lander ES, Linton LM, Birren B et al (2001) Initial sequencing and analysis of the human genome. Nature 409(6822):860–921. doi:10.1038/35057062 PubMedCrossRefGoogle Scholar
  13. 13.
    Jensen LE, Whitehead AS (2004) The 3′ untranslated region of the membrane-bound IL-1R accessory protein mRNA confers tissue-specific destabilization. J Immunol 173(10):6248–6258PubMedGoogle Scholar
  14. 14.
    To KK, Robey RW, Knutsen T, Zhan Z, Ried T, Bates SE (2009) Escape from hsa-miR-519c enables drug-resistant cells to maintain high expression of ABCG2. Mol Cancer Ther 8(10):2959–2968. doi:10.1158/1535-7163.mct-09-0292 PubMedCrossRefGoogle Scholar
  15. 15.
    To KK, Zhan Z, Litman T, Bates SE (2008) Regulation of ABCG2 expression at the 3′ untranslated region of its mRNA through modulation of transcript stability and protein translation by a putative microRNA in the S1 colon cancer cell line. Mol Cell Biol 28(17):5147–5161. doi:10.1128/mcb.00331-08 PubMedCrossRefGoogle Scholar
  16. 16.
    Wang F, Xue X, Wei J, An Y, Yao J, Cai H, Wu J, Dai C, Qian Z, Xu Z, Miao Y (2010) hsa-miR-520h downregulates ABCG2 in pancreatic cancer cells to inhibit migration, invasion, and side populations. Br J Cancer 103(4):567–574. doi:10.1038/sj.bjc.6605724 PubMedCrossRefGoogle Scholar
  17. 17.
    Pan YZ, Morris ME, Yu AM (2009) MicroRNA-328 negatively regulates the expression of breast cancer resistance protein (BCRP/ABCG2) in human cancer cells. Mol Pharmacol 75(6):1374–1379. doi:10.1124/mol.108.054163 PubMedCrossRefGoogle Scholar
  18. 18.
    Ciafre SA, Galardi S, Mangiola A, Ferracin M, Liu CG, Sabatino G, Negrini M, Maira G, Croce CM, Farace MG (2005) Extensive modulation of a set of microRNAs in primary glioblastoma. Biochem Biophys Res Commun 334(4):1351–1358. doi:10.1016/j.bbrc.2005.07.030 PubMedCrossRefGoogle Scholar
  19. 19.
    Neilson JR, Zheng GX, Burge CB, Sharp PA (2007) Dynamic regulation of miRNA expression in ordered stages of cellular development. Genes Dev 21(5):578–589. doi:10.1101/gad.1522907 PubMedCrossRefGoogle Scholar
  20. 20.
    Maillot G, Lacroix-Triki M, Pierredon S, Gratadou L, Schmidt S, Benes V, Roche H, Dalenc F, Auboeuf D, Millevoi S, Vagner S (2009) Widespread estrogen-dependent repression of micrornas involved in breast tumor cell growth. Cancer Res 69(21):8332–8340. doi:10.1158/0008-5472.can-09-2206 PubMedCrossRefGoogle Scholar
  21. 21.
    Yao Y, Suo AL, Li ZF, Liu LY, Tian T, Ni L, Zhang WG, Nan KJ, Song TS, Huang C (2009) MicroRNA profiling of human gastric cancer. Mol Med Report 2(6):963–970. doi:10.3892/mmr_00000199 Google Scholar
  22. 22.
    Nurul-Syakima AM, Yoke-Kqueen C, Sabariah AR, Shiran MS, Singh A, Learn-Han L (2011) Differential microRNA expression and identification of putative miRNA targets and pathways in head and neck cancers. Int J Mol Med 28(3):327–336. doi:10.3892/ijmm.2011.714 PubMedGoogle Scholar
  23. 23.
    Marton S, Garcia MR, Robello C, Persson H, Trajtenberg F, Pritsch O, Rovira C, Naya H, Dighiero G, Cayota A (2008) Small RNAs analysis in CLL reveals a deregulation of miRNA expression and novel miRNA candidates of putative relevance in CLL pathogenesis. Leukemia 22(2):330–338. doi:10.1038/sj.leu.2405022 PubMedCrossRefGoogle Scholar
  24. 24.
    Fei J, Li Y, Zhu X, Luo X (2012) miR-181a post-transcriptionally downregulates oncogenic RalA and contributes to growth inhibition and apoptosis in chronic myelogenous leukemia (CML). PLoS ONE 7(3):e32834. doi:10.1371/journal.pone.0032834 PubMedCrossRefGoogle Scholar
  25. 25.
    Galluzzi L, Morselli E, Vitale I, Kepp O, Senovilla L, Criollo A, Servant N, Paccard C, Hupe P, Robert T, Ripoche H, Lazar V, Harel-Bellan A, Dessen P, Barillot E, Kroemer G (2010) miR-181a and miR-630 regulate cisplatin-induced cancer cell death. Cancer Res 70(5):1793–1803. doi:10.1158/0008-5472.can-09-3112 PubMedCrossRefGoogle Scholar
  26. 26.
    Ke G, Liang L, Yang JM, Huang X, Han D, Huang S, Zhao Y, Zha R, He X, Wu X (2012) MiR-181a confers resistance of cervical cancer to radiation therapy through targeting the pro-apoptotic PRKCD gene. Oncogene. doi:10.1038/onc.2012.323 Google Scholar
  27. 27.
    Li H, Hui L, Xu W (2012) miR-181a sensitizes a multidrug-resistant leukemia cell line K562/A02 to daunorubicin by targeting BCL-2. Acta Biochim Biophys Sin (Shanghai) 44(3):269–277. doi:10.1093/abbs/gmr128 CrossRefGoogle Scholar
  28. 28.
    Bai H, Cao Z, Deng C, Zhou L, Wang C (2012) miR-181a sensitizes resistant leukaemia HL-60/Ara-C cells to Ara-C by inducing apoptosis. J Cancer Res Clin Oncol 138(4):595–602. doi:10.1007/s00432-011-1137-3 PubMedCrossRefGoogle Scholar
  29. 29.
    Guo LJ, Zhang QY (2012) Decreased serum miR-181a is a potential new tool for breast cancer screening. Int J Mol Med 30(3):680–686. doi:10.3892/ijmm.2012.1021 PubMedGoogle Scholar
  30. 30.
    Taylor MA, Sossey-Alaoui K, Thompson CL, Danielpour D, Schiemann WP (2013) TGF-beta upregulates miR-181a expression to promote breast cancer metastasis. J Clin Invest 123(1):150–163. doi:10.1172/jci64946 PubMedCrossRefGoogle Scholar
  31. 31.
    Li S, Yang C, Zhai L, Zhang W, Yu J, Gu F, Lang R, Fan Y, Gong M, Zhang X, Fu L (2012) Deep sequencing reveals small RNA characterization of invasive micropapillary carcinomas of the breast. Breast Cancer Res Treat 136(1):77–87. doi:10.1007/s10549-012-2166-6 PubMedCrossRefGoogle Scholar
  32. 32.
    Tekirdag KA, Korkmaz G, Ozturk DG, Agami R, Gozuacik D (2013) MIR181A regulates starvation- and rapamycin-induced autophagy through targeting of ATG5. Autophagy 9(3):374–385PubMedCrossRefGoogle Scholar
  33. 33.
    de Hoon MJ, Imoto S, Nolan J, Miyano S (2004) Open source clustering software. Bioinformatics 20(9):1453–1454. doi:10.1093/bioinformatics/bth078 PubMedCrossRefGoogle Scholar
  34. 34.
    Saldanha AJ (2004) Java treeview–extensible visualization of microarray data. Bioinformatics 20(17):3246–3248. doi:10.1093/bioinformatics/bth349 PubMedCrossRefGoogle Scholar
  35. 35.
    Liang Z, Wu H, Xia J, Li Y, Zhang Y, Huang K, Wagar N, Yoon Y, Cho HT, Scala S, Shim H (2010) Involvement of miR-326 in chemotherapy resistance of breast cancer through modulating expression of multidrug resistance-associated protein 1. Biochem Pharmacol 79(6):817–824. doi:10.1016/j.bcp.2009.10.017 PubMedCrossRefGoogle Scholar
  36. 36.
    Peng H, Dong Z, Qi J, Yang Y, Liu Y, Li Z, Xu J, Zhang JT (2009) A novel two mode-acting inhibitor of ABCG2-mediated multidrug transport and resistance in cancer chemotherapy. PLoS ONE 4(5):e5676. doi:10.1371/journal.pone.0005676 PubMedCrossRefGoogle Scholar
  37. 37.
    Pogribny IP, Filkowski JN, Tryndyak VP, Golubov A, Shpyleva SI, Kovalchuk O (2010) Alterations of microRNAs and their targets are associated with acquired resistance of MCF-7 breast cancer cells to cisplatin. Int J Cancer 127(8):1785–1794. doi:10.1002/ijc.25191 PubMedCrossRefGoogle Scholar
  38. 38.
    Ward A, Balwierz A, Zhang JD, Kublbeck M, Pawitan Y, Hielscher T, Wiemann S, Sahin O (2012) Re-expression of microRNA-375 reverses both tamoxifen resistance and accompanying EMT-like properties in breast cancer. Oncogene. doi:10.1038/onc.2012.128 Google Scholar
  39. 39.
    Cuesta R, Martinez-Sanchez A, Gebauer F (2009) miR-181a regulates cap-dependent translation of p27(kip1) mRNA in myeloid cells. Mol Cell Biol 29(10):2841–2851. doi:10.1128/mcb.01971-08 PubMedCrossRefGoogle Scholar
  40. 40.
    Zhang X, Nie Y, Du Y, Cao J, Shen B, Li Y (2012) MicroRNA-181a promotes gastric cancer by negatively regulating tumor suppressor KLF6. Tumour Biol 33(5):1589–1597. doi:10.1007/s13277-012-0414-3 PubMedCrossRefGoogle Scholar
  41. 41.
    Shin KH, Bae SD, Hong HS, Kim RH, Kang MK, Park NH (2011) miR-181a shows tumor suppressive effect against oral squamous cell carcinoma cells by downregulating K-ras. Biochem Biophys Res Commun 404(4):896–902. doi:10.1016/j.bbrc.2010.12.055 PubMedCrossRefGoogle Scholar
  42. 42.
    Brangi M, Litman T, Ciotti M, Nishiyama K, Kohlhagen G, Takimoto C, Robey R, Pommier Y, Fojo T, Bates SE (1999) Camptothecin resistance: role of the ATP-binding cassette (ABC), mitoxantrone-resistance half-transporter (MXR), and potential for glucuronidation in MXR-expressing cells. Cancer Res 59(23):5938–5946PubMedGoogle Scholar
  43. 43.
    Wander SA, Zhao D, Besser AH, Hong F, Wei J, Ince TA, Milikowski C, Bishopric NH, Minn AJ, Creighton CJ, Slingerland JM (2013) PI3K/mTOR inhibition can impair tumor invasion and metastasis in vivo despite a lack of antiproliferative action in vitro: implications for targeted therapy. Breast Cancer Res Treat 138(2):369–381. doi:10.1007/s10549-012-2389-6 PubMedCrossRefGoogle Scholar
  44. 44.
    Mercatelli N, Coppola V, Bonci D, Miele F, Costantini A, Guadagnoli M, Bonanno E, Muto G, Frajese GV, De Maria R, Spagnoli LG, Farace MG, Ciafre SA (2008) The inhibition of the highly expressed miR-221 and miR-222 impairs the growth of prostate carcinoma xenografts in mice. PLoS ONE 3(12):e4029. doi:10.1371/journal.pone.0004029 PubMedCrossRefGoogle Scholar
  45. 45.
    Hou J, Lin L, Zhou W, Wang Z, Ding G, Dong Q, Qin L, Wu X, Zheng Y, Yang Y, Tian W, Zhang Q, Wang C, Zhuang SM, Zheng L, Liang A, Tao W, Cao X (2011) Identification of miRNomes in human liver and hepatocellular carcinoma reveals miR-199a/b-3p as therapeutic target for hepatocellular carcinoma. Cancer Cell 19(2):232–243. doi:10.1016/j.ccr.2011.01.001 PubMedCrossRefGoogle Scholar
  46. 46.
    Fedier A, Schwarz VA, Walt H, Carpini RD, Haller U, Fink D (2001) Resistance to topoisomerase poisons due to loss of DNA mismatch repair. Int J Cancer 93(4):571–576PubMedCrossRefGoogle Scholar
  47. 47.
    Lu H, Hallstrom TC (2012) Sensitivity to TOP2 targeting chemotherapeutics is regulated by Oct1 and FILIP1L. PLoS ONE 7(8):e42921. doi:10.1371/journal.pone.0042921 PubMedCrossRefGoogle Scholar
  48. 48.
    Goler-Baron V, Sladkevich I, Assaraf YG (2012) Inhibition of the PI3K-Akt signaling pathway disrupts ABCG2-rich extracellular vesicles and overcomes multidrug resistance in breast cancer cells. Biochem Pharmacol 83(10):1340–1348. doi:10.1016/j.bcp.2012.01.033 PubMedCrossRefGoogle Scholar
  49. 49.
    Ji J, Yamashita T, Wang XW (2011) Wnt/beta-catenin signaling activates microRNA-181 expression in hepatocellular carcinoma. Cell Biosci 1(1):4. doi:10.1186/2045-3701-1-4 PubMedCrossRefGoogle Scholar
  50. 50.
    Bisso A, Faleschini M, Zampa F, Capaci V, De Santa J, Santarpia L, Piazza S, Cappelletti V, Daidone M, Agami R, Del Sal G (2013) Oncogenic miR-181a/b affect the DNA damage response in aggressive breast cancer. Cell Cycle 12(11):251–266CrossRefGoogle Scholar
  51. 51.
    Zhu DX, Zhu W, Fang C, Fan L, Zou ZJ, Wang YH, Liu P, Hong M, Miao KR, Xu W, Li JY (2012) miR-181a/b significantly enhances drug sensitivity in chronic lymphocytic leukemia cells via targeting multiple anti-apoptosis genes. Carcinogenesis 33(7):1294–1301. doi:10.1093/carcin/bgs179 PubMedCrossRefGoogle Scholar
  52. 52.
    Su SF, Chang YW, Andreu-Vieyra C, Fang JY, Yang Z, Han B, Lee AS, Liang G (2012) miR-30d, miR-181a and miR-199a-5p cooperatively suppress the endoplasmic reticulum chaperone and signaling regulator GRP78 in cancer. Oncogene. doi:10.1038/onc.2012.483 Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Xuyang Jiao
    • 1
  • Lin Zhao
    • 1
  • Mengtao Ma
    • 1
  • Xuefeng Bai
    • 1
  • Miao He
    • 1
  • Yuanyuan Yan
    • 1
  • Yan Wang
    • 1
  • Qiuchen Chen
    • 1
  • Xinnan Zhao
    • 1
  • Mingyi Zhou
    • 1
  • Zeshi Cui
    • 3
  • Zhihong Zheng
    • 2
  • Enhua Wang
    • 2
  • Minjie Wei
    • 1
    • 2
  1. 1.Department of PharmacologyChina Medical UniversityShenyangChina
  2. 2.Institute of Pathology and PathophysiologyChina Medical UniversityShenyangChina
  3. 3.Center of Laboratory Technology and Experimental MedicineChina Medical UniversityShenyangChina

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