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High miR-21 expression in breast cancer associated with poor disease-free survival in early stage disease and high TGF-β1

  • Epidemiology
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Abstract

MicroRNA-21 (miR-21) is considered an onco-microRNA given its abilities to suppress the actions of several tumor suppressor genes and to promote tumor cell growth, invasion and metastasis. Recently, transforming growth factor-beta (TGF-β) is found to up-regulate the expression of miR-21, and elevated miR-21 expression is seen frequently in breast cancer. To evaluate the effect of miR-21 on disease progression and its association with TGF-β, we analyzed miR-21 expression in breast cancer. Fresh tumor samples were collected during surgery from 344 patients diagnosed with primary breast cancer. The expression of miR-21 in tumor samples was measured with a TaqMan® microRNA assay using U6 as reference. Levels of miR-21 expression by disease stage, tumor grade, histology, hormone receptor status and lymph node involvement were compared. Cox proportional hazards regression analysis was performed to assess the association of miR-21 expression with disease-free and overall survival. The study results showed that the expression of miR-21 was detected in all tumor samples with substantial variation. High miR-21 expression was associated with features of aggressive disease, including high tumor grade, negative hormone receptor status, and ductal carcinoma. High miR-21 was also positively correlated with TGF-β1. No associations were found between patient survival and miR-21 expression among all patients, but high miR-21 was associated with poor disease-free survival in early stage patients (HR = 2.08, 95% CI: 1.08–4.00) despite no value for prognosis. The study supports the notion that miR-21 is an onco-microRNA for breast cancer. Elevated miR-21 expression may facilitate tumor progression, and TGF-β may up-regulate its expression.

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References

  1. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297. doi:10.1016/S0092-8674(04)00045-5

    Article  PubMed  CAS  Google Scholar 

  2. Esquela-Kerscher A, Slack FJ (2006) Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer 6(4):259–269. doi:10.1038/nrc1840

    Article  PubMed  CAS  Google Scholar 

  3. Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, Aldler H, Rattan S, Keating M, Rai K, Rassenti L, Kipps T, Negrini M, Bullrich F, Croce CM (2002) Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 99(24):15524–15529. doi:10.1073/pnas.242606799

    Article  PubMed  CAS  Google Scholar 

  4. Sempere LF, Christensen M, Silahtaroglu A, Bak M, Heath CV, Schwartz G, Wells W, Kauppinen S, Cole CN (2007) Altered MicroRNA expression confined to specific epithelial cell subpopulations in breast cancer. Cancer Res 67(24):11612–11620. doi:10.1158/0008-5472.CAN-07-5019

    Article  PubMed  CAS  Google Scholar 

  5. Inamura K, Togashi Y, Nomura K, Ninomiya H, Hiramatsu M, Satoh Y, Okumura S, Nakagawa K, Ishikawa Y (2007) let-7 microRNA expression is reduced in bronchioloalveolar carcinoma, a non-invasive carcinoma, and is not correlated with prognosis. Lung Cancer 58(3):392–396. doi:10.1016/j.lungcan.2007.07.013

    Article  PubMed  Google Scholar 

  6. Fang WJ, Lin CZ, Zhang HH, Qian J, Zhong L, Xu N (2007) Detection of let-7a microRNA by real-time PCR in colorectal cancer: a single-centre experience from China. J Int Med Res 35(5):716–723

    PubMed  CAS  Google Scholar 

  7. Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, Magri E, Pedriali M, Fabbri M, Campiglio M et al (2005) MicroRNA gene expression deregulation in human breast cancer. Cancer Res 65(16):7065–7070. doi:10.1158/0008-5472.CAN-05-1783

    Article  PubMed  CAS  Google Scholar 

  8. Slaby O, Svoboda M, Fabian P, Smerdova T, Knoflickova D, Bednarikova M, Nenutil R, Vyzula R (2007) Altered expression of miR-21, miR-31, miR-143 and miR-145 is related to clinicopathologic features of colorectal cancer. Oncology 72(5–6):397–402. doi:10.1159/000113489

    Article  PubMed  CAS  Google Scholar 

  9. Schetter AJ, Leung SY, Sohn JJ, Zanetti KA, Bowman ED, Yanaihara N, Yuen ST, Chan TL, Kwong DL, Au GK et al (2008) MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA 299(4):425–436. doi:10.1001/jama.299.4.425

    Article  PubMed  CAS  Google Scholar 

  10. Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, Stephens RM, Okamoto A, Yokota J, Tanaka T et al (2006) Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 9(3):189–198. doi:10.1016/j.ccr.2006.01.025

    Article  PubMed  CAS  Google Scholar 

  11. Markou A, Tsaroucha EG, Kaklamanis L, Fotinou M, Georgoulias V, Lianidou ES (2008) Prognostic value of mature microRNA-21 and microRNA-205 overexpression in non-small cell lung cancer by quantitative real-time RT-PCR. Clin Chem 54(10):1696–1704

    Article  PubMed  CAS  Google Scholar 

  12. Roldo C, Missiaglia E, Hagan JP, Falconi M, Capelli P, Bersani S, Calin GA, Volinia S, Liu CG, Scarpa A et al (2006) MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior. J Clin Oncol 24(29):4677–4684. doi:10.1200/JCO.2005.05.5194

    Article  PubMed  CAS  Google Scholar 

  13. Dillhoff M, Liu J, Frankel W, Croce C, Bloomston M (2008) MicroRNA-21 is overexpressed in pancreatic cancer and a potential predictor of survival. J Gastrointest Surg. Jul 19. doi:10.1007/s11605-008-0584-x

  14. Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M et al (2006) A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA 103(7):2257–2261. doi:10.1073/pnas.0510565103

    Article  PubMed  CAS  Google Scholar 

  15. Chan JA, Krichevsky AM, Kosik KS (2005) MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res 65(14):6029–6033. doi:10.1158/0008-5472.CAN-05-0137

    Article  PubMed  CAS  Google Scholar 

  16. Meng F, Henson R, Lang M, Wehbe H, Maheshwari S, Mendell JT, Jiang J, Schmittgen TD, Patel T (2006) Involvement of human micro-RNA in growth and response to chemotherapy in human cholangiocarcinoma cell lines. Gastroenterology 130(7):2113–2129. doi:10.1053/j.gastro.2006.02.057

    Article  PubMed  CAS  Google Scholar 

  17. Si ML, Zhu S, Wu H, Lu Z, Wu F, Mo YY (2007) miR-21-mediated tumor growth. Oncogene 26(19):2799–2803. doi:10.1038/sj.onc.1210083

    Article  PubMed  CAS  Google Scholar 

  18. Zhu S, Si ML, Wu H, Mo YY (2007) MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). J Biol Chem 282(19):14328–14336. doi:10.1074/jbc.M611393200

    Article  PubMed  CAS  Google Scholar 

  19. Frankel LB, Christoffersen NR, Jacobsen A, Lindow M, Krogh A, Lund AH (2008) Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells. J Biol Chem 283(2):1026–1033. doi:10.1074/jbc.M707224200

    Article  PubMed  CAS  Google Scholar 

  20. Zhu S, Wu H, Wu F, Nie D, Sheng S, Mo YY (2008) MicroRNA-21 targets tumor suppressor genes in invasion and metastasis. Cell Res 18(3):350–359. doi:10.1038/cr.2008.24

    Article  PubMed  CAS  Google Scholar 

  21. Davis BN, Hilyard AC, Lagna G, Hata A (2008) SMAD proteins control DROSHA-mediated microRNA maturation. Nature 454(7200):56–61. doi:10.1038/nature07086

    Article  PubMed  CAS  Google Scholar 

  22. Li C, Guo B, Bernabeu C, Kumar S (2001) Angiogenesis in breast cancer: the role of transforming growth factor beta and CD105. Microsc Res Tech 52(4):437–449. doi:10.1002/1097-0029(20010215)52:4<437::AID-JEMT1029>3.0.CO;2-G

    Article  PubMed  CAS  Google Scholar 

  23. Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T (2007) MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 133(2):647–658. doi:10.1053/j.gastro.2007.05.022

    Article  PubMed  CAS  Google Scholar 

  24. Edwin F Sr, Endersby R, Baker SJ, Patel TB (2006) The tumor suppressor PTEN is necessary for human Sprouty 2-mediated inhibition of cell proliferation. J Biol Chem 281(8):4816–4822. doi:10.1074/jbc.M508300200

    Article  PubMed  CAS  Google Scholar 

  25. Sayed D, Rane S, Lypowy J, He M, Chen IY, Vashistha H, Yan L, Malhotra A, Vatner D, Abdellatif M (2008) MicroRNA-21 targets sprouty2 and promotes cellular outgrowths. Mol Biol Cell 19(8):3272–3282

    Article  PubMed  CAS  Google Scholar 

  26. Lo TL, Yusoff P, Fong CW, Guo K, McCaw BJ, Phillips WA, Yang H, Wong ES, Leong HF, Zeng Q, Putti TC, Guy GR (2004) The ras/mitogen-activated protein kinase pathway inhibitor and likely tumor suppressor proteins, sprouty 1 and sprouty 2 are deregulated in breast cancer. Cancer Res 64(17):6127–6136. doi:10.1158/0008-5472.CAN-04-1207

    Article  PubMed  CAS  Google Scholar 

  27. Asangani IA, Rasheed SA, Nikolova DA, Leupold JH, Colburn NH, Post S, Allgayer H (2008) MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene 27(15):2128–2136. doi:10.1038/sj.onc.1210856

    Article  PubMed  CAS  Google Scholar 

  28. Camps C, Buffa FM, Colella S, Moore J, Sotiriou C, Sheldon H, Harris AL, Gleadle JM, Ragoussis J (2008) hsa-miR-210 Is induced by hypoxia and is an independent prognostic factor in breast cancer. Clin Cancer Res 14(5):1340–1348. doi:10.1158/1078-0432.CCR-07-1755

    Article  PubMed  CAS  Google Scholar 

  29. Mu L, Katsaros D, Lu L, Preti M, Durando A, Arisio R, Yu H (2008) TGF-B1 genotype and phenotype in breast cancer and their associations with IGFs and patient survival. Br J Cancer. Sep 30. doi:10.1038/sj.bjc.6004689

  30. Akhurst RJ, Derynck R (2001) TGF-beta signaling in cancer—a double-edged sword. Trends Cell Biol 11(11):S44–S51. doi:10.1016/S0962-8924(01)02130-4

    Article  PubMed  CAS  Google Scholar 

  31. Siegel PM, Massagué J (2003) Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nat Rev Cancer 3(11):807–821. doi:10.1038/nrc1208

    Article  PubMed  CAS  Google Scholar 

  32. ten Dijke P, Arthur HM (2007) Extracellular control of TGFbeta signalling in vascular development and disease. Nat Rev Mol Cell Biol 8(11):857–869. doi:10.1038/nrm2262

    Article  PubMed  CAS  Google Scholar 

  33. Pardali K, Moustakas A (2007) Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer. Biochim Biophys Acta 1775(1):21–62

    PubMed  CAS  Google Scholar 

  34. Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M et al (2004) Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA 101(9):2999–3004. doi:10.1073/pnas.0307323101

    Article  PubMed  CAS  Google Scholar 

  35. Calin GA, Croce CM (2007) Chromosomal rearrangements and microRNAs: a new cancer link with clinical implications. J Clin Invest 117(8):2059–2066. doi:10.1172/JCI32577

    Article  PubMed  CAS  Google Scholar 

  36. Lawrie CH, Soneji S, Marafioti T, Cooper CD, Palazzo S, Paterson JC, Cattan H, Enver T, Mager R, Boultwood J et al (2007) MicroRNA expression distinguishes between germinal center B cell-like and activated B cell-like subtypes of diffuse large B cell lymphoma. Int J Cancer 121(5):1156–1161. doi:10.1002/ijc.22800

    Article  PubMed  CAS  Google Scholar 

  37. Ladeiro Y, Couchy G, Balabaud C, Bioulac-Sage P, Pelletier L, Rebouissou S, Zucman-Rossi J (2008) MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations. Hepatology 47(6):1955–1963. doi:10.1002/hep.22256

    Article  PubMed  CAS  Google Scholar 

  38. Connolly E, Melegari M, Landgraf P, Tchaikovskaya T, Tennant BC, Slagle BL, Rogler LE, Zavolan M, Tuschl T, Rogler CE (2008) Elevated expression of the miR-17–92 polycistron and miR-21 in hepadnavirus-associated hepatocellular carcinoma contributes to the malignant phenotype. Am J Pathol 173(3):856–864. doi:10.2353/ajpath.2008.080096

    Article  PubMed  CAS  Google Scholar 

  39. Chan SH, Wu CW, Li AF, Chi CW, Lin WC (2008) miR-21 microRNA expression in human gastric carcinomas and its clinical association. Anticancer Res 28(2A):907-911

    PubMed  Google Scholar 

  40. Feber A, Xi L, Luketich JD, Pennathur A, Landreneau RJ, Wu M, Swanson SJ, Godfrey TE, Litle VR (2008) MicroRNA expression profiles of esophageal cancer. J Thorac Cardiovasc Surg 135(2):255-260. discussion 260. doi:10.1016/j.jtcvs.2007.08.055

    Article  PubMed  CAS  Google Scholar 

  41. Nam EJ, Yoon H, Kim SW, Kim H, Kim YT, Kim JH, Kim JW, Kim S (2008) MicroRNA expression profiles in serous ovarian carcinoma. Clin Cancer Res 14(9):2690–2695. doi:10.1158/1078-0432.CCR-07-1731

    Article  PubMed  CAS  Google Scholar 

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Author notes

  1. Lina Mu

    Present address: Department of Social and Preventive Medicine, School of Public Health and Health Professions, University at Buffalo, The State University of New York, Buffalo, NY, 14214, USA

Authors and Affiliations

  1. Department of Epidemiology and Public Health, Yale Cancer Center, Yale University School of Medicine, 60 College Street, New Haven, CT, 06520-8034, USA

    Biyun Qian, Lingeng Lu, Lina Mu & Herbert Yu

  2. Tianjin Medical University Cancer Institute and Hospital, Tianjin, China

    Biyun Qian

  3. Department of Obstetrics and Gynecology, Gynecologic Oncology and Breast Cancer Unit, University of Turin, Turin, Italy

    Dionyssios Katsaros, Mario Preti & Antonio Durando

  4. Department of Pathology, S’Anna Hospital, Turin, Italy

    Riccardo Arisio

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  1. Biyun Qian
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Correspondence to Herbert Yu.

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Qian, B., Katsaros, D., Lu, L. et al. High miR-21 expression in breast cancer associated with poor disease-free survival in early stage disease and high TGF-β1. Breast Cancer Res Treat 117, 131–140 (2009). https://doi.org/10.1007/s10549-008-0219-7

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  • DOI: https://doi.org/10.1007/s10549-008-0219-7

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