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Complexity in Regulation of microRNA Machinery Components in Invasive Breast Carcinoma

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Pathology & Oncology Research

Abstract

Altered expression of microRNA (miRNA) machinery components may play an important role in breast cancer progression. The objective of the current study was to evaluate Drosha, the DiGeorge syndrome critical region gene 8 (DGCR8), Dicer, and Argonaute 2 (AGO2) mRNA expression in invasive breast carcinoma (IBC) and to assess the value of clinical parameters on their expression. By using quantitative real-time PCR, we examined the expression of the four miRNA machinery components in 52 breast tumor tissues which are diagnosed as invasive ductal carcinoma and adjacent non-neoplastic tissues. In the present study, decreased mRNA expression levels of major miRNA machinery components were observed in IBC. The altered mRNA expression levels of DGCR8 and AGO2 are positively correlated with to each other. This study revealed for the first time that expression alterations of DGCR8 are significantly associated with estrogen receptor and Ki-67 status in IBC. Moreover, AGO2 mRNA expression level was significantly correlated with N stage. These results provided evidences that down-regulated the four miRNA machinery components may play an important role in breast pathobiology and that DGCR8 and AGO2 might be associated with important clinical factors.

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References

  1. Abd El-Rehim DM, Ball G, Pinder SE, Rakha E, Paish C, Robertson JF, Macmillan D, Blamey RW, Ellis IO (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):340–350. doi:10.1002/ijc.21004

    Article  CAS  PubMed  Google Scholar 

  2. Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L, Akslen LA, Ragaz J, Gown AM, Gilks CB, van de Rijn M, Perou CM (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10(16):5367–5374. doi:10.1158/1078-0432.CCR-04-0220

    Article  CAS  PubMed  Google Scholar 

  3. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752. doi:10.1038/35021093

    Article  CAS  PubMed  Google Scholar 

  4. Rakha EA, Reis-Filho JS, Ellis IO (2008) Basal-like breast cancer: a critical review. J Clin Oncol 26(15):2568–2581. doi:10.1200/JCO.2007.13.1748

    Article  PubMed  Google Scholar 

  5. Diaz LK, Cryns VL, Symmans WF, Sneige N (2007) Triple negative breast carcinoma and the basal phenotype: from expression profiling to clinical practice. Adv Anat Pathol 14(6):419–430. doi:10.1097/PAP.0b013e3181594733

    Article  CAS  PubMed  Google Scholar 

  6. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Lonning PE, Borresen-Dale AL (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98(19):10869–10874. doi:10.1073/pnas.191367098

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Yerushalmi R, Woods R, Ravdin PM, Hayes MM, Gelmon KA (2010) Ki67 in breast cancer: prognostic and predictive potential. Lancet Oncol 11(2):174–183. doi:10.1016/S1470-2045(09)70262-1

    Article  CAS  PubMed  Google Scholar 

  8. Dowsett M, Nielsen TO, A'Hern R, Bartlett J, Coombes RC, Cuzick J, Ellis M, Henry NL, Hugh JC, Lively T, McShane L, Paik S, Penault-Llorca F, Prudkin L, Regan M, Salter J, Sotiriou C, Smith IE, Viale G, Zujewski JA, Hayes DF, International Ki-67 in Breast Cancer Working G (2011) Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. J Natl Cancer Inst 103(22):1656–1664. doi:10.1093/jnci/djr393

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297

    Article  CAS  PubMed  Google Scholar 

  10. Papachristou DJ, Korpetinou A, Giannopoulou E, Antonacopoulou AG, Papadaki H, Grivas P, Scopa CD, Kalofonos HP (2011) Expression of the ribonucleases Drosha, Dicer, and Ago2 in colorectal carcinomas. Virchows Arch Int J Pathol 459(4):431–440. doi:10.1007/s00428-011-1119-5

    Article  CAS  Google Scholar 

  11. Mockenhaupt S, Schurmann N, Grimm D (2011) When cellular networks run out of control: global dysregulation of the RNAi machinery in human pathology and therapy. Prog Mol Biol Transl Sci 102:165–242. doi:10.1016/B978-0-12-415795-8.00006-4

    Article  CAS  PubMed  Google Scholar 

  12. Lee Y, Han J, Yeom KH, Jin H, Kim VN (2006) Drosha in primary microRNA processing. Cold Spring Harb Symp Quant Biol 71:51–57. doi:10.1101/sqb.2006.71.041

    Article  CAS  PubMed  Google Scholar 

  13. Gregory RI, Yan KP, Amuthan G, Chendrimada T, Doratotaj B, Cooch N, Shiekhattar R (2004) The Microprocessor complex mediates the genesis of microRNAs. Nature 432(7014):235–240. doi:10.1038/nature03120

    Article  CAS  PubMed  Google Scholar 

  14. Tijsterman M, Plasterk RH (2004) Dicers at RISC; the mechanism of RNAi. Cell 117(1):1–3

    Article  CAS  PubMed  Google Scholar 

  15. Sand M, Skrygan M, Georgas D, Arenz C, Gambichler T, Sand D, Altmeyer P, Bechara FG (2012) Expression levels of the microRNA maturing microprocessor complex component DGCR8 and the RNA-induced silencing complex (RISC) components argonaute-1, argonaute-2, PACT, TARBP1, and TARBP2 in epithelial skin cancer. Mol Carcinog 51(11):916–922. doi:10.1002/mc.20861

    Article  CAS  PubMed  Google Scholar 

  16. Merritt WM, Lin YG, Han LY, Kamat AA, Spannuth WA, Schmandt R, Urbauer D, Pennacchio LA, Cheng JF, Nick AM, Deavers MT, Mourad-Zeidan A, Wang H, Mueller P, Lenburg ME, Gray JW, Mok S, Birrer MJ, Lopez-Berestein G, Coleman RL, Bar-Eli M, Sood AK (2008) Dicer, Drosha, and outcomes in patients with ovarian cancer. N Engl J Med 359(25):2641–2650. doi:10.1056/NEJMoa0803785

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Kim B, Lee JH, Park JW, Kwon TK, Baek SK, Hwang I, Kim S (2013) An essential microRNA maturing microprocessor complex component DGCR8 is up-regulated in colorectal carcinomas. Clin Exp Med. doi:10.1007/s10238-013-0243-8

    Google Scholar 

  18. Grelier G, Voirin N, Ay AS, Cox DG, Chabaud S, Treilleux I, Leon-Goddard S, Rimokh R, Mikaelian I, Venoux C, Puisieux A, Lasset C, Moyret-Lalle C (2009) Prognostic value of Dicer expression in human breast cancers and association with the mesenchymal phenotype. Br J Cancer 101(4):673–683. doi:10.1038/sj.bjc.6605193

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Dedes KJ, Natrajan R, Lambros MB, Geyer FC, Lopez-Garcia MA, Savage K, Jones RL, Reis-Filho JS (2011) Down-regulation of the miRNA master regulators Drosha and Dicer is associated with specific subgroups of breast cancer. Eur J Cancer 47(1):138–150. doi:10.1016/j.ejca.2010.08.007

    Article  CAS  PubMed  Google Scholar 

  20. Passon N, Gerometta A, Puppin C, Lavarone E, Puglisi F, Tell G, Di Loreto C, Damante G (2012) Expression of Dicer and Drosha in triple-negative breast cancer. J Clin Pathol 65(4):320–326. doi:10.1136/jclinpath-2011-200496

    Article  CAS  PubMed  Google Scholar 

  21. Yan M, Huang HY, Wang T, Wan Y, Cui SD, Liu ZZ, Fan QX (2012) Dysregulated expression of dicer and drosha in breast cancer. Pathol Oncol Res 18(2):343–348. doi:10.1007/s12253-011-9450-3

    Article  CAS  PubMed  Google Scholar 

  22. Khoshnaw SM, Rakha EA, Abdel-Fatah TM, Nolan CC, Hodi Z, Macmillan DR, Ellis IO, Green AR (2012) Loss of Dicer expression is associated with breast cancer progression and recurrence. Breast Cancer Res Treat 135(2):403–413. doi:10.1007/s10549-012-2169-3

    Article  CAS  PubMed  Google Scholar 

  23. Chiosea S, Jelezcova E, Chandran U, Acquafondata M, McHale T, Sobol RW, Dhir R (2006) Up-regulation of dicer, a component of the MicroRNA machinery, in prostate adenocarcinoma. Am J Pathol 169(5):1812–1820. doi:10.2353/ajpath.2006.060480

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Sugito N, Ishiguro H, Kuwabara Y, Kimura M, Mitsui A, Kurehara H, Ando T, Mori R, Takashima N, Ogawa R, Fujii Y (2006) RNASEN regulates cell proliferation and affects survival in esophageal cancer patients. Clin Cancer Res 12(24):7322–7328. doi:10.1158/1078-0432.CCR-06-0515

    Article  CAS  PubMed  Google Scholar 

  25. Martin MG, Payton JE, Link DC (2009) Dicer and outcomes in patients with acute myeloid leukemia (AML). Leuk Res 33(8):e127. doi:10.1016/j.leukres.2009.02.003

    Article  PubMed  Google Scholar 

  26. Harvey JM, Clark GM, Osborne CK, Allred DC (1999) Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17(5):1474–1481

    CAS  PubMed  Google Scholar 

  27. Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, Press MF, Spears PA, Vance GH, Viale G, Hayes DF (2013) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: american society of clinical oncology/college of american pathologists clinical practice guideline update. J Clin Oncol 31(31):3997–4013. doi:10.1200/JCO.2013.50.9984

    Article  PubMed  Google Scholar 

  28. Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 3(6):1101–1108

    Article  CAS  PubMed  Google Scholar 

  29. Shen J, Stass SA, Jiang F (2012) MicroRNAs as potential biomarkers in human solid tumors. Cancer Lett. doi:10.1016/j.canlet.2012.11.001

    Google Scholar 

  30. Li PY, He FC, Zhou GQ (2011) Association of human microRNA related genetic variations with cancer. Yi chuan = Hereditas/Zhongguo yi chuan xue hui bian ji 33(8):870–878

    Article  CAS  PubMed  Google Scholar 

  31. Schmittgen TD (2008) Regulation of microRNA processing in development, differentiation and cancer. J Cell Mol Med 12(5B):1811–1819. doi:10.1111/j.1582-4934.2008.00483.x

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Han L, Zhang A, Zhou X, Xu P, Wang GX, Pu PY, Kang CS (2010) Downregulation of Dicer enhances tumor cell proliferation and invasion. Int J Oncol 37(2):299–305

    CAS  PubMed  Google Scholar 

  33. Faggad A, Budczies J, Tchernitsa O, Darb-Esfahani S, Sehouli J, Muller BM, Wirtz R, Chekerov R, Weichert W, Sinn B, Mucha C, Elwali NE, Schafer R, Dietel M, Denkert C (2010) Prognostic significance of Dicer expression in ovarian cancer-link to global microRNA changes and oestrogen receptor expression. J Pathol 220(3):382–391. doi:10.1002/path.2658

    CAS  PubMed  Google Scholar 

  34. Cheng C, Fu X, Alves P, Gerstein M (2009) mRNA expression profiles show differential regulatory effects of microRNAs between estrogen receptor-positive and estrogen receptor-negative breast cancer. Genome Biol 10(9):R90. doi:10.1186/gb-2009-10-9-r90

    Article  PubMed Central  PubMed  Google Scholar 

  35. Erson AE, Petty EM (2009) miRNAs and cancer: new research developments and potential clinical applications. Cancer Biol Ther 8(24):2317–2322

    Article  CAS  PubMed  Google Scholar 

  36. Yu Z, Baserga R, Chen L, Wang C, Lisanti MP, Pestell RG (2010) microRNA, cell cycle, and human breast cancer. Am J Pathol 176(3):1058–1064. doi:10.2353/ajpath.2010.090664

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Caudle AS, Yi M, Hoffman KE, Mittendorf EA, Babiera GV, Hwang RF, Meric-Bernstam F, Sahin AA, Hunt KK (2013) Impact of identification of internal mammary sentinel lymph node metastasis in breast cancer patients. Ann Surg Oncol. doi:10.1245/s10434-013-3276-z

    Google Scholar 

  38. Liu Y, Yin W, Yan T, Du Y, Shao Z, Lu J (2013) The clinical significance of Ki-67 as a marker of prognostic value and chemosensitivity prediction in hormone-receptor-positive breast cancer: a meta-analysis of the published literature. Curr Med Res Opin. doi:10.1185/03007995.2013.833088

    Google Scholar 

  39. Pathmanathan N, Balleine RL (2013) Ki67 and proliferation in breast cancer. J Clin Pathol 66(6):512–516. doi:10.1136/jclinpath-2012-201085

    Article  CAS  PubMed  Google Scholar 

  40. Foulkes WD, Smith IE, Reis-Filho JS (2010) Triple-negative breast cancer. N Engl J Med 363(20):1938–1948. doi:10.1056/NEJMra1001389

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The biospecimens for this study were provided by the Keimyung Human Bio-Resource Bank, a member of the National Biobank of Korea, which is supported by the Ministry of Health and Welfare. All samples derived from the National Biobank of Korea were obtained with informed consent under institutional review board-approved protocols.

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Authors and Affiliations

  1. Department of Pathology, School of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu, 704-701, South Korea

    Sun Young Kwon

  2. Department of Anatomy, School of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu, 704-701, South Korea

    Jae-ho Lee

  3. Department of Immunology, School of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu, 704-701, South Korea

    Bora Kim, Jong-Wook Park, Taeg Kyu Kwon & Shin Kim

  4. Department of Surgery, School of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu, 704-701, South Korea

    Sun Hee Kang

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  1. Sun Young Kwon
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Correspondence to Shin Kim.

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Sun Young Kwon and Jae-ho Lee contributed equally to this work.

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Kwon, S.Y., Lee, Jh., Kim, B. et al. Complexity in Regulation of microRNA Machinery Components in Invasive Breast Carcinoma. Pathol. Oncol. Res. 20, 697–705 (2014). https://doi.org/10.1007/s12253-014-9750-5

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