Breast Cancer Research and Treatment

, Volume 135, Issue 2, pp 403–413 | Cite as

Loss of Dicer expression is associated with breast cancer progression and recurrence

  • Sarkawt M. Khoshnaw
  • Emad A. Rakha
  • Tarek M. Abdel-Fatah
  • Christopher C. Nolan
  • Zsolt Hodi
  • Douglas R. Macmillan
  • Ian O. Ellis
  • Andrew R. Green
Preclinical Study


Dicer is a protein that plays a pivotal role in the final steps of the microRNA (miRNA) processing pathway, to produce mature miRNAs from their precursor molecules. The purpose of the current study was to assess the biological and prognostic value of Dicer protein expression in breast cancer (BC). Dicer protein expression was assessed immunohistochemically in two sets of BC: (1) full-face sections of selected BC series with distinct stages of tumour progression (normal, in situ (DCIS), primary invasive BC and nodal metastases) to evaluate its differential expression. (2) Tissue microarray comprising a large and well-characterised series of unselected clinically annotated invasive BC (n = 1,174) to investigate its correlation with clinicopathological features and patient outcome. A gradual loss of Dicer protein expression was observed in malignant compared to normal breast tissues, with the loss being the least in DCIS and most prominent in metastatic malignant cells. In invasive BC, loss of Dicer expression was associated with features of aggressive behaviour including higher histological grade, loss of hormone receptor and BRCA1 protein expression and with shorter disease-free survival (DFS). Dicer expression was an independent predictor of recurrence in the aggressive HER2-positive subgroup. Moreover, loss of Dicer was predictive of better response to chemotherapy and to endocrine therapy. This study provides evidence that Dicer protein plays a role in human BC progression and behaviour, and assessment of its expression could provide prognostic information in BC including the HER2-positive class.


Breast cancer Dicer expression Tumour progression Outcome 


Conflicts of interest

The authors have no conflicts of interest.


  1. 1.
    Reinhart BJ et al (2000) The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403(6772):901–906PubMedCrossRefGoogle Scholar
  2. 2.
    Hutvagner G et al (2001) A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science 293(5531):834–838PubMedCrossRefGoogle Scholar
  3. 3.
    Khoshnaw SM et al (2009) MicroRNA involvement in the pathogenesis and management of breast cancer. J Clin Pathol 62(5):422–428PubMedCrossRefGoogle Scholar
  4. 4.
    Bernstein E et al (2001) Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409(6818):363–366PubMedCrossRefGoogle Scholar
  5. 5.
    Lau PW et al (2012) The molecular architecture of human Dicer. Nat Struct Mol Biol 19(4):436–440PubMedCrossRefGoogle Scholar
  6. 6.
    Lee YS et al (2004) Distinct roles for Drosophila Dicer-1 and Dicer-2 in the siRNA/miRNA silencing pathways. Cell 117(1):69–81PubMedCrossRefGoogle Scholar
  7. 7.
    Houghton J et al (2004) Gastric cancer originating from bone marrow-derived cells. Science 306(5701):1568–1571PubMedCrossRefGoogle Scholar
  8. 8.
    Bernstein E et al (2003) Dicer is essential for mouse development. Nat Genet 35(3):215–217PubMedCrossRefGoogle Scholar
  9. 9.
    Fukagawa T et al (2004) Dicer is essential for formation of the heterochromatin structure in vertebrate cells. Nat Cell Biol 6(8):784–791PubMedCrossRefGoogle Scholar
  10. 10.
    Murchison EP et al (2005) Characterization of Dicer-deficient murine embryonic stem cells. Proc Natl Acad Sci USA 102(34):12135–12140PubMedCrossRefGoogle Scholar
  11. 11.
    Blenkiron C et al (2007) MicroRNA expression profiling of human breast cancer identifies new markers of tumor subtype. Genome Biol 8(10):R214PubMedCrossRefGoogle Scholar
  12. 12.
    Zheng ZH et al (2007) Decreased expression of Dicer-1 in gastric cancer. Chin Med J (Engl) 120(23):2099–2104Google Scholar
  13. 13.
    Karube Y et al (2005) Reduced expression of Dicer associated with poor prognosis in lung cancer patients. Cancer Sci 96(2):111–115PubMedCrossRefGoogle Scholar
  14. 14.
    Kumar MS et al (2009) Dicer-1 functions as a haploinsufficient tumor suppressor. Genes Dev 23(23):2700–2704PubMedCrossRefGoogle Scholar
  15. 15.
    Martello G et al (2010) A microRNA targeting dicer for metastasis control. Cell 141(7):1195–1207PubMedCrossRefGoogle Scholar
  16. 16.
    Chiosea S et al (2007) Overexpression of Dicer in precursor lesions of lung adenocarcinoma. Cancer Res 67(5):2345–2350PubMedCrossRefGoogle Scholar
  17. 17.
    Wong MP et al (2002) Primary adenocarcinomas of the lung in nonsmokers show a distinct pattern of allelic imbalance. Cancer Res 62(15):4464–4468PubMedGoogle Scholar
  18. 18.
    Zhang L et al (2006) microRNAs exhibit high frequency genomic alterations in human cancer. Proc Natl Acad Sci USA 103(24):9136–9141PubMedCrossRefGoogle Scholar
  19. 19.
    Rakha EA et al (2006) Morphological and immunophenotypic analysis of breast carcinomas with basal and myoepithelial differentiation. J Pathol 208(4):495–506Google Scholar
  20. 20.
    Rakha EA et al (2007) Prognostic markers in triple-negative breast cancer. Cancer 109(1):25–32PubMedCrossRefGoogle Scholar
  21. 21.
    Rakha EA et al (2005) Expression of mucins (MUC1, MUC2, MUC3, MUC4, MUC5AC and MUC6) and their prognostic significance in human breast cancer. Mod Pathol 18(10):1295–1304PubMedCrossRefGoogle Scholar
  22. 22.
    Abd El-Rehim DM et al (2005) High-throughput protein expression analysis using tissue microarray technology of a large well-characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses. Int J Cancer 116(3):340–350PubMedCrossRefGoogle Scholar
  23. 23.
    Rakha EA et al (2009) Triple-negative breast cancer: distinguishing between basal and nonbasal subtypes. Clin Cancer Res 15(7):2302–2310PubMedCrossRefGoogle Scholar
  24. 24.
    Galea MH et al (1992) The Nottingham Prognostic Index in primary breast cancer. Breast Cancer Res Treat 22(3):207–219PubMedCrossRefGoogle Scholar
  25. 25.
    El-Rehim DM et al (2004) Expression and co-expression of the members of the epidermal growth factor receptor (EGFR) family in invasive breast carcinoma. Br J Cancer 91(8):1532–1542CrossRefGoogle Scholar
  26. 26.
    Rakha EA et al (2010) Clinical and biological significance of E-cadherin protein expression in invasive lobular carcinoma of the breast. Am J Surg Pathol 34(10):1472–1479PubMedCrossRefGoogle Scholar
  27. 27.
    Kononen J et al (1998) Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4(7):844–847PubMedCrossRefGoogle Scholar
  28. 28.
    Flavin RJ et al (2008) Altered eIF6 and Dicer expression is associated with clinicopathological features in ovarian serous carcinoma patients. Mod Pathol 21(6):676–684PubMedCrossRefGoogle Scholar
  29. 29.
    McCarty KS Jr et al (1985) Estrogen receptor analyses. Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med 109(8):716–721PubMedGoogle Scholar
  30. 30.
    McShane L et al (2006) REporting recommendations for tumor MARKer prognostic studies (REMARK)Google Scholar
  31. 31.
    Grelier G et al (2009) Prognostic value of Dicer expression in human breast cancers and association with the mesenchymal phenotype. Br J Cancer 101(4):673–683PubMedCrossRefGoogle Scholar
  32. 32.
    Vaksman O et al (2012) Argonaute, Dicer, and Drosha are up-regulated along tumor progression in serous ovarian carcinoma. Hum Pathol. doi: 10.1016/j.humpath.2012.02.016
  33. 33.
    Passon N et al (2012) Expression of Dicer and Drosha in triple-negative breast cancer. J Clin Pathol 65:320–326PubMedCrossRefGoogle Scholar
  34. 34.
    Lee Y et al (2002) MicroRNA maturation: stepwise processing and subcellular localization. EMBO J 21(17):4663–4670PubMedCrossRefGoogle Scholar
  35. 35.
    Somasundaram K (2003) Breast cancer gene 1 (BRCA1): role in cell cycle regulation and DNA repair–perhaps through transcription. J Cell Biochem 88(6):1084–1091PubMedCrossRefGoogle Scholar
  36. 36.
    Paull TT et al (2001) Direct DNA binding by BRCA1. Proc Natl Acad Sci USA 98(11):6086–6091PubMedCrossRefGoogle Scholar
  37. 37.
    Moskwa P et al (2011) miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors. Mol Cell 41(2):210–220PubMedCrossRefGoogle Scholar
  38. 38.
    Garcia AI et al (2011) Down-regulation of BRCA1 expression by miR-146a and miR-146b-5p in triple negative sporadic breast cancers. EMBO Mol Med 3(5):279–290PubMedCrossRefGoogle Scholar
  39. 39.
    Heyn H et al (2011) MicroRNA miR-335 is crucial for the BRCA1 regulatory cascade in breast cancer development. Int J Cancer 129(12):2797–2806PubMedCrossRefGoogle Scholar
  40. 40.
    Faggad A et al (2010) Prognostic significance of Dicer expression in ovarian cancer-link to global microRNA changes and oestrogen receptor expression. J Pathol 220(3):382–391PubMedGoogle Scholar
  41. 41.
    Chiosea S et al (2006) Up-regulation of dicer, a component of the MicroRNA machinery, in prostate adenocarcinoma. Am J Pathol 169(5):1812–1820PubMedCrossRefGoogle Scholar
  42. 42.
    Chiosea SI et al (2008) Mucoepidermoid carcinoma of upper aerodigestive tract: clinicopathologic study of 78 cases with immunohistochemical analysis of Dicer expression. Virchows Arch 452(6):629–635PubMedCrossRefGoogle Scholar
  43. 43.
    Cheng C et al (2009) mRNA expression profiles show differential regulatory effects of microRNAs between estrogen receptor-positive and estrogen receptor-negative breast cancer. Genome Biol 10(9):R90PubMedCrossRefGoogle Scholar
  44. 44.
    Dedes KJ et al (2011) Down-regulation of the miRNA master regulators Drosha and Dicer is associated with specific subgroups of breast cancer. Eur J Cancer 47(1):138–150PubMedCrossRefGoogle Scholar
  45. 45.
    Yan M et al (2011) Dysregulated expression of Dicer and Drosha in breast cancer. Pathol Oncol Res 18:343–348PubMedCrossRefGoogle Scholar
  46. 46.
    Shu GS, Yang ZL, Liu DC (2012) Immunohistochemical study of Dicer and Drosha expression in the benign and malignant lesions of gallbladder and their clinicopathological significances. Pathol Res Pract 208(7):392–397Google Scholar
  47. 47.
    Lin RJ et al (2010) microRNA signature and expression of Dicer and Drosha can predict prognosis and delineate risk groups in neuroblastoma. Cancer Res 70(20):7841–7850PubMedCrossRefGoogle Scholar
  48. 48.
    Noh H et al (2011) Impaired microRNA processing facilitates breast cancer cell invasion by upregulating urokinase-type plasminogen activator expression. Genes Cancer 2(2):140–150PubMedCrossRefGoogle Scholar
  49. 49.
    Faber C et al (2011) Overexpression of Dicer predicts poor survival in colorectal cancer. Eur J Cancer 47(9):1414–1419PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Sarkawt M. Khoshnaw
    • 1
  • Emad A. Rakha
    • 1
  • Tarek M. Abdel-Fatah
    • 1
  • Christopher C. Nolan
    • 1
  • Zsolt Hodi
    • 1
  • Douglas R. Macmillan
    • 1
  • Ian O. Ellis
    • 1
  • Andrew R. Green
    • 1
  1. 1.Department of HistopathologySchool of Molecular Medical Sciences, University of Nottingham and Nottingham University Hospitals NHS TrustNottinghamUK

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