Skip to main content

Advertisement

SpringerLink
Log in

miR-221/222: promising biomarkers for breast cancer

  • Review
  • Published:
Tumor Biology

Abstract

MicroRNAs (miRNAs) are small noncoding RNAs of 19–25 nt that can regulate gene expression at a posttranscriptional level. Increasing evidence indicates that miRNAs participate in almost every step of cellular processes and are often aberrantly expressed in human cancer. miR-221 and miR-222 are two highly homologous miRNAs that always act as a gene cluster (miR-221/222) in cellular regulation and have extensively been studied in cancer network. Here, we review the role of miR-221/222 in breast cancer (BCa) development and progression: regulating proliferative signaling pathways, altering telomere and telomerase activity, avoiding cell death from tumor suppressors, autophagy and apoptosis, monitoring angiogenesis, supporting epithelial–mesenchymal transition, and even controlling cell-specific function within microenvironment. We consider that miR-221/222 act as promising biomarkers for BCa and they would offer a new way in molecular targeting cancer treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136(2):215–33.

    Article  PubMed  CAS  Google Scholar 

  2. Kong YW, Ferland-McCollough D, Jackson TJ, Bushell M. microRNAs in cancer management. Lancet Oncol. 2012;13(6):e249–58.

    Article  PubMed  CAS  Google Scholar 

  3. O'Day E, Lal A. MicroRNAs and their target gene networks in breast cancer. Breast Cancer Res. 2010;12(2):201.

    Article  PubMed  Google Scholar 

  4. Blenkiron C, Goldstein LD, Thorne NP, Spiteri I, Chin SF, Dunning MJ, et al. MicroRNA expression profiling of human breast cancer identifies new markers of tumor subtype. Genome Biol. 2007;8(10):R214.

    Article  PubMed  Google Scholar 

  5. Garofalo M, Quintavalle C, Romano G, Croce CM, Condorelli G. miR221/222 in cancer: their role in tumor progression and response to therapy. Curr Mol Med. 2012;12(1):27–33.

    Article  PubMed  CAS  Google Scholar 

  6. Howe EN, Cochrane DR, Richer JK. The miR-200 and miR-221/222 microRNA families: opposing effects on epithelial identity. J Mammary Gland Biol Neoplasia. 2012;17(1):65–77.

    Article  PubMed  Google Scholar 

  7. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    Article  PubMed  CAS  Google Scholar 

  8. Miller TE, Ghoshal K, Ramaswamy B, Roy S, Datta J, Shapiro CL, et al. MicroRNA-221/222 confers tamoxifen resistance in breast cancer by targeting p27Kip1. J Biol Chem. 2008;283(44):29897–903.

    Article  PubMed  CAS  Google Scholar 

  9. Zhao JJ, Lin J, Yang H, Kong W, He L, Ma X, et al. MicroRNA-221/222 negatively regulates estrogen receptor alpha and is associated with tamoxifen resistance in breast cancer. J Biol Chem. 2008;283(45):31079–86.

    Article  PubMed  CAS  Google Scholar 

  10. Cochrane DR, Cittelly DM, Howe EN, Spoelstra NS, McKinsey EL, LaPara K, et al. MicroRNAs link estrogen receptor alpha status and Dicer levels in breast cancer. Horm Cancer. 2010;1(6):306–19.

    Article  PubMed  CAS  Google Scholar 

  11. Zhao R, Wu J, Jia W, Gong C, Yu F, Ren Z, et al. Plasma miR-221 as a predictive biomarker for chemoresistance in breast cancer patients who previously received neoadjuvant chemotherapy. Onkologie. 2011;34(12):675–80.

    Article  PubMed  CAS  Google Scholar 

  12. García-Becerra R, Santos N, Díaz L, Camacho J. Mechanisms of resistance to endocrine therapy in breast cancer: focus on signaling pathways, miRNAs and genetically based resistance. Int J Mol Sci. 2012;14(1):108–45.

    Article  PubMed  Google Scholar 

  13. Manavalan TT, Teng Y, Appana SN, Datta S, Kalbfleisch TS, Li Y, et al. Differential expression of microRNA expression in tamoxifen-sensitive MCF-7 versus tamoxifen-resistant LY2 human breast cancer cells. Cancer Lett. 2011;313(1):26–43.

    Article  PubMed  CAS  Google Scholar 

  14. Lu Y, Roy S, Nuovo G, Ramaswamy B, Miller T, Shapiro C, et al. Anti-microRNA-222 (anti-miR-222) and -181B suppress growth of tamoxifen-resistant xenografts in mouse by targeting TIMP3 protein and modulating mitogenic signal. J Biol Chem. 2011;286(49):42292–302.

    Article  PubMed  CAS  Google Scholar 

  15. Di Leva G, Gasparini P, Piovan C, Ngankeu A, Garofalo M, Taccioli C, et al. MicroRNA cluster 221–222 and estrogen receptor alpha interactions in breast cancer. J Natl Cancer Inst. 2010;102(10):706–21.

    Article  PubMed  Google Scholar 

  16. McCafferty MP, McNeill RE, Miller N, Kerin MJ. Interactions between the estrogen receptor, its cofactors and microRNAs in breast cancer. Breast Cancer Res Treat. 2009;116(3):425–32.

    Article  PubMed  CAS  Google Scholar 

  17. Rao X, Di Leva G, Li M, Fang F, Devlin C, Hartman-Frey C, et al. MicroRNA-221/222 confers breast cancer fulvestrant resistance by regulating multiple signaling pathways. Oncogene. 2011;30(9):1082–97.

    Article  PubMed  CAS  Google Scholar 

  18. Yoshimoto N, Toyama T, Takahashi S, Sugiura H, Endo Y, Iwasa M, et al. Distinct expressions of microRNAs that directly target estrogen receptor α in human breast cancer. Breast Cancer Res Treat. 2011;130(1):331–9.

    Article  PubMed  CAS  Google Scholar 

  19. Leung YK, Lee MT, Lam HM, Tarapore P, Ho SM. Estrogen receptor-beta and breast cancer: translating biology into clinical practice. Steroids. 2012;77(7):727–37.

    Article  PubMed  CAS  Google Scholar 

  20. Wärnmark A, Almlöf T, Leers J, Gustafsson JA, Treuter E. Differential recruitment of the mammalian mediator subunit TRAP220 by estrogen receptors ERalpha and ERbeta. J Biol Chem. 2001;276(26):23397–404.

    Article  PubMed  Google Scholar 

  21. Yang Z, Barnes CJ, Kumar R. Human epidermal growth factor receptor 2 status modulates subcellular localization of and interaction with estrogen receptor alpha in breast cancer cells. Clin Cancer Res. 2004;10(11):3621–8.

    Article  PubMed  CAS  Google Scholar 

  22. Stinson S, Lackner MR, Adai AT, Yu N, Kim HJ, O'Brien C, et al. TRPS1 targeting by miR-221/222 promotes the epithelial-to-mesenchymal transition in breast cancer. Sci Signal. 2011;4(177):ra41.

    Article  PubMed  Google Scholar 

  23. Cui J, Germer K, Wu T, Wang J, Luo J, Wang SC, et al. Cross-talk between HER2 and MED1 regulates tamoxifen resistance of human breast cancer cells. Cancer Res. 2012;72(21):5625–34.

    Article  PubMed  CAS  Google Scholar 

  24. Vargas J, Feltes BC, Poloni Jde F, Lenz G, Bonatto D. Senescence: an endogenous anticancer mechanism. Front Biosci. 2012;17:2616–43.

    Article  PubMed  Google Scholar 

  25. Nabetani A, Ishikawa F. Alternative lengthening of telomeres pathway: recombination-mediated telomere maintenance mechanism in human cells. J Biochem. 2011;149(1):5–14.

    Article  PubMed  CAS  Google Scholar 

  26. Cheung AL, Deng W. Telomere dysfunction, genome instability and cancer. Front Biosci. 2008;13:2075–90.

    Article  PubMed  CAS  Google Scholar 

  27. Benetti R, Gonzalo S, Jaco I, Muñoz P, Gonzalez S, Schoeftner S, et al. A mammalian microRNA cluster controls DNA methylation and telomere recombination via Rbl2-dependent regulation of DNA methyltransferases. Nat Struct Mol Biol. 2008;15(3):268–79.

    Article  PubMed  CAS  Google Scholar 

  28. Romilda C, Marika P, Alessandro S, Enrico L, Marina B, Andromachi K, et al. Oxidative DNA damage correlates with cell immortalization and miR-92 expression in hepatocellular carcinoma. BMC Cancer. 2012;12:177.

    Article  PubMed  Google Scholar 

  29. Cairney CJ, Keith WN. Telomerase redefined: integrated regulation of hTR and hTERT for telomere maintenance and telomerase activity. Biochimie. 2008;90(1):13–23.

    Article  PubMed  CAS  Google Scholar 

  30. Mitomo S, Maesawa C, Ogasawara S, Iwaya T, Shibazaki M, Yashima-Abo A, et al. Downregulation of miR-138 is associated with overexpression of human telomerase reverse transcriptase protein in human anaplastic thyroid carcinoma cell lines. Cancer Sci. 2008;99(2):280–6.

    Article  PubMed  CAS  Google Scholar 

  31. Lu L, Zhang C, Zhu G, Irwin M, Risch H, Menato G, et al. Telomerase expression and telomere length in breast cancer and their associations with adjuvant treatment and disease outcome. Breast Cancer Res. 2011;13(3):R56.

    Article  PubMed  CAS  Google Scholar 

  32. Winnikow EP, Medeiros LR, Edelweiss MI, Rosa DD, Edelweiss M, Simões PW, et al. Accuracy of telomerase in estimating breast cancer risk: a systematic review and meta-analysis. Breast. 2012;21(1):1–7.

    Article  PubMed  Google Scholar 

  33. Shen J, Gammon MD, Terry MB, Bradshaw PT, Wang Q, Teitelbaum SL, et al. Genetic polymorphisms in telomere pathway genes, telomere length, and breast cancer survival. Breast Cancer Res Treat. 2012;134(1):393–400.

    Article  PubMed  Google Scholar 

  34. Lu X, Zhao P, Zhang C, Fu Z, Chen Y, Lu A, et al. Analysis of miR-221 and p27 expression in human gliomas. Mol Med Rep. 2009;2(4):651–6.

    PubMed  CAS  Google Scholar 

  35. Pineau P, Volinia S, McJunkin K, Marchio A, Battiston C, Terris B, et al. miR-221 overexpression contributes to liver tumorigenesis. Proc Natl Acad Sci. 2010;107(1):264–9.

    Article  PubMed  CAS  Google Scholar 

  36. Galardi S, Mercatelli N, Giorda E, Massalini S, Frajese GV, Ciafrè SA, et al. miR-221 and miR-222 expression affects the proliferation potential of human prostate carcinoma cell lines by targeting p27Kip1. J Biol Chem. 2007;282(32):23716–24.

    Article  PubMed  CAS  Google Scholar 

  37. Kedde M, van Kouwenhove M, Zwart W, Oude Vrielink JA, Elkon R, Agami RA. Pumilio-induced RNA structure switch in p27-3′ UTR controls miR-221 and miR-222 accessibility. Nat Cell Biol. 2010;12(10):1014–20.

    Article  PubMed  CAS  Google Scholar 

  38. Garofalo M, Di Leva G, Romano G, Nuovo G, Suh SS, Ngankeu A, et al. miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. Cancer Cell. 2009;16(6):498–509.

    Article  PubMed  CAS  Google Scholar 

  39. Chen Y, Zaman MS, Deng G, Majid S, Saini S, Liu J, et al. MicroRNAs 221/222 and genistein-mediated regulation of ARHI tumor suppressor gene in prostate cancer. Cancer Prev Res (Phila). 2011;4(1):76–86.

    Article  CAS  Google Scholar 

  40. Vousden KH, Prives C. Blinded by the light: the growing complexity of p53. Cell. 2009;137(3):413–31.

    Article  PubMed  CAS  Google Scholar 

  41. Frankel LB, Lund AH. MicroRNA regulation of autophagy. Carcinogenesis. 2012;33(11):2018–25.

    Article  PubMed  CAS  Google Scholar 

  42. Pyo JO, Nah J, Jung YK. Molecules and their functions in autophagy. Exp Mol Med. 2012;44(2):73–80.

    Article  PubMed  CAS  Google Scholar 

  43. Noren Hooten N, Abdelmohsen K, Gorospe M, Ejiogu N, Zonderman AB, Evans MK. microRNA expression patterns reveal differential expression of target genes with age. PLoS One. 2010;5(5):e10724.

    Article  PubMed  Google Scholar 

  44. Gramantieri L, Fornari F, Ferracin M, Veronese A, Sabbioni S, Calin GA, et al. MicroRNA-221 targets Bmf in hepatocellular carcinoma and correlates with tumor multifocality. Clin Cancer Res. 2009;15(16):5073–81.

    Article  PubMed  CAS  Google Scholar 

  45. Zhang C, Zhang J, Zhang A, Wang Y, Han L, You Y, et al. PUMA is a novel target of miR-221/222 in human epithelial cancers. Int J Oncol. 2010;37(6):1621–6.

    PubMed  CAS  Google Scholar 

  46. Guttilla IK, Phoenix KN, Hong X, Tirnauer JS, Claffey KP, White BA. Prolonged mammosphere culture of MCF-7 cells induces an EMT and repression of the estrogen receptor by microRNAs. Breast Cancer Res Treat. 2012;132(1):75–85.

    Article  PubMed  CAS  Google Scholar 

  47. Aschrafi A, Schwechter AD, Mameza MG, Natera-Naranjo O, Gioio AE, Kaplan BB. MicroRNA-338 regulates local cytochrome c oxidase IV mRNA levels and oxidative phosphorylation in the axons of sympathetic neurons. J Neurosci. 2008;28(47):12581–90.

    Article  PubMed  CAS  Google Scholar 

  48. Gong M, Chen Y, Senturia R, Ulgherait M, Faller M, Guo F. Caspases cleave and inhibit the microRNA processing protein DiGeorge Critical Region 8. Protein Sci. 2012;21(6):797–808.

    Article  PubMed  CAS  Google Scholar 

  49. Urbich C, Kuehbacher A, Dimmeler S. Role of microRNAs in vascular diseases, inflammation, and angiogenesis. Cardiovasc Res. 2008;79(4):581–8.

    Article  PubMed  CAS  Google Scholar 

  50. Rippe C, Blimline M, Magerko KA, Lawson BR, LaRocca TJ, Donato AJ, et al. MicroRNA changes in human arterial endothelial cells with senescence: relation to apoptosis, eNOS and inflammation. Exp Gerontol. 2012;47(1):45–51.

    Article  PubMed  CAS  Google Scholar 

  51. Durán WN, Breslin JW, Sánchez FA. The NO cascade, eNOS location, and microvascular permeability. Cardiovasc Res. 2010;87(2):254–61.

    Article  PubMed  Google Scholar 

  52. Suárez Y, Fernández-Hernando C, Pober JS, Sessa WC. Dicer dependent microRNAs regulate gene expression and functions in human endothelial cells. Circ Res. 2007;100(8):1164–73.

    Article  PubMed  Google Scholar 

  53. Chen Y, Banda M, Speyer CL, Smith JS, Rabson AB, Gorski DH. Regulation of the expression and activity of the antiangiogenic homeobox gene GAX/MEOX2 by ZEB2 and microRNA-221. Mol Cell Biol. 2010;30(15):3902–13.

    Article  PubMed  CAS  Google Scholar 

  54. Liu X, Cheng Y, Yang J, Xu L, Zhang C. Cell-specific effects of miR-221/222 in vessels: molecular mechanism and therapeutic application. J Mol Cell Cardiol. 2012;52(1):245–55.

    Article  PubMed  CAS  Google Scholar 

  55. Liu X, Cheng Y, Zhang S, Lin Y, Yang J, Zhang C. A necessary role of miR-221 and miR-222 in vascular smooth muscle cell proliferation and neointimal hyperplasia. Circ Res. 2009;104(4):476–87.

    Article  PubMed  CAS  Google Scholar 

  56. Poliseno L, Tuccoli A, Mariani L, Evangelista M, Citti L, Woods K, et al. MicroRNAs modulate the angiogenic properties of HUVECs. Blood. 2006;108(9):3068–71.

    Article  PubMed  CAS  Google Scholar 

  57. Noonan DM, De Lerma BA, Vannini N, Mortara L, Albini A. Inflammation, inflammatory cells and angiogenesis: decisions and indecisions. Cancer Metastasis Rev. 2008;27(1):31–40.

    Article  PubMed  Google Scholar 

  58. Dentelli P, Rosso A, Orso F, Olgasi C, Taverna D, Brizzi MF. microRNA-222 controls neovascularization by regulating signal transducer and activator of transcription 5A expression. Arterioscler Thromb Vasc Biol. 2010;30(8):1562–8.

    Article  PubMed  CAS  Google Scholar 

  59. Zhu N, Zhang D, Chen S, Liu X, Lin L, Huang X, et al. Endothelial enriched microRNAs regulate angiotensin II-induced endothelial inflammation and migration. Atherosclerosis. 2011;215(2):286–93.

    Article  PubMed  CAS  Google Scholar 

  60. Gao D, Vahdat LT, Wong S, Chang JC, Mittal V. Microenvironmental regulation of epithelial–mesenchymal transitions in cancer. Cancer Res. 2012;72(19):4883–9.

    Article  PubMed  CAS  Google Scholar 

  61. Shah MY, Calin GA. MicroRNAs miR-221 and miR-222: a new level of regulation in aggressive breast cancer. Genome Med. 2011;3(8):56.

    Article  PubMed  Google Scholar 

  62. Radojicic J, Zaravinos A, Vrekoussis T, Kafousi M, Spandidos DA, Stathopoulos EN. MicroRNA expression analysis in triple-negative (ER, PR and Her2/neu) breast cancer. Cell Cycle. 2011;10(3):507–17.

    Article  PubMed  CAS  Google Scholar 

  63. Wellner U, Schubert J, Burk UC, Schmalhofer O, Zhu F, Sonntag A, et al. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol. 2009;11(12):1487–95.

    Article  PubMed  CAS  Google Scholar 

  64. de Herreros AG, Peiró S, Nassour M, Savagner P. Snail family regulation and epithelial mesenchymal transitions in breast cancer progression. J Mammary Gland Biol Neoplasia. 2010;15(2):135–47.

    Article  PubMed  Google Scholar 

  65. Sleeman JP, Thiery JP. SnapShot: the epithelial–mesenchymal transition. Cell. 2011;145(1):162.

    Article  PubMed  CAS  Google Scholar 

  66. Lambertini E, Lolli A, Vezzali F, Penolazzi L, Gambari R, Piva R. Correlation between Slug transcription factor and miR-221 in MDA-MB-231 breast cancer cells. BMC Cancer. 2012;12:445.

    Article  PubMed  CAS  Google Scholar 

  67. Ye Y, Xiao Y, Wang W, Yearsley K, Gao JX, Shetuni B, et al. ER alpha signaling through slug regulates E-cadherin and EMT. Oncogene. 2010;29(10):1451–62.

    Article  PubMed  CAS  Google Scholar 

  68. Grelier G, Voirin N, Ay AS, Cox DG, Chabaud S, Treilleux I, et al. Prognostic value of Dicer expression in human breast cancers and association with the mesenchymal phenotype. Br J Cancer. 2009;101(4):673–83.

    Article  PubMed  CAS  Google Scholar 

  69. Heldin CH, Vanlandewijck M, Moustakas A. Regulation of EMT by TGFβ in cancer. FEBS Lett. 2012;586(14):1959–70.

    Article  PubMed  CAS  Google Scholar 

  70. Mayoral RJ, Pipkin ME, Pachkov M, van Nimwegen E, Rao A, Monticelli S. MicroRNA-221-222 regulate the cell cycle in mast cells. J Immunol. 2009;182(1):433–45.

    PubMed  CAS  Google Scholar 

  71. Mayoral RJ, Deho L, Rusca N, Bartonicek N, Saini HK, Enright AJ, et al. MiR-221 influences effector functions and actin cytoskeleton in mast cells. PLoS One. 2011;6(10):e26133.

    Article  PubMed  CAS  Google Scholar 

  72. Lu C, Huang X, Zhang X, Roensch K, Cao Q, Nakayama KI, et al. miR-221 and miR-155 regulate human dendritic cell development, apoptosis, and IL-12 production through targeting of p27kip1, KPC1, and SOCS-1. Blood. 2011;117(16):4293–303.

    Article  PubMed  CAS  Google Scholar 

  73. Zhao L, Sun Y, Hou Y, Peng Q, Wang L, Luo H, et al. MiRNA expression analysis of cancer-associated fibroblasts and normal fibroblasts in breast cancer. Int J Biochem Cell Biol. 2012;44(11):2051–9.

    Article  PubMed  CAS  Google Scholar 

  74. Brognara E, Fabbri E, Aimi F, Manicardi A, Bianchi N, Finotti A, et al. Peptide nucleic acids targeting miR-221 modulate p27Kip1 expression in breast cancer MDA-MB-231 cells. Int J Oncol. 2012;41(6):2119–27.

    PubMed  CAS  Google Scholar 

  75. Kim JK, Choi KJ, Lee M, Jo MH, Kim S. Molecular imaging of a cancer-targeting theragnostics probe using a nucleolin aptamer- and microRNA-221 molecular beacon-conjugated nanoparticle. Biomaterials. 2012;33(1):207–17.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work has no fund. We thank Shan-Liang Zhong, MD and Jin-Jin Xu, MD for their discussions and help in revision.

Conflicts of interest

None

Author information

Authors and Affiliations

  1. The Fourth Clinical College of Nanjing Medical University, Nanjing, China

    Wei-Xian Chen & Man-Tang Qiu

  2. The Graduate School of Xuzhou Medical College, Xuzhou, China

    Qing Hu

  3. Department of General Surgery, Nanjing Medical University Affiliated Cancer Hospital Cancer Institute of Jiangsu Province, Nanjing, China

    Wei-Xian Chen, Qing Hu & Jin-Hai Tang

  4. Center of Clinical Laboratory, Nanjing Medical University Affiliated Cancer Hospital Cancer Institute of Jiangsu Province, Nanjing, China

    Shan-Liang Zhong, Jin-Jin Xu & Jian-Hua Zhao

  5. Baiziting 42, Nanjing, China, 210009

    Jin-Hai Tang & Jian-Hua Zhao

Authors
  1. Wei-Xian Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qing Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Man-Tang Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shan-Liang Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jin-Jin Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jin-Hai Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jian-Hua Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jin-Hai Tang or Jian-Hua Zhao.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, WX., Hu, Q., Qiu, MT. et al. miR-221/222: promising biomarkers for breast cancer. Tumor Biol. 34, 1361–1370 (2013). https://doi.org/10.1007/s13277-013-0750-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-013-0750-y

Keywords

Search

Navigation