Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Cellular Oncology
Published in: Cellular Oncology 3/2014

01-06-2014 | Original Paper

Differential expression of miR-139, miR-486 and miR-21 in breast cancer patients sub-classified according to lymph node status

Authors: Lene Rask, Eva Balslev, Rolf Søkilde, Estrid Høgdall, Henrik Flyger, Jens Eriksen, Thomas Litman

Published in: Cellular Oncology | Issue 3/2014

Login to get access

Abstract

Purpose

Therapeutic decisions in breast cancer are increasingly guided by prognostic and predictive biomarkers. Non-protein-coding microRNAs (miRNAs) have recently been found to be deregulated in breast cancers and, in addition, to be correlated with several clinico-pathological features. One of the most consistently up-regulated miRNAs is miR-21. Here, we specifically searched for differentially expressed miRNAs in high-risk breast cancer patients as compared to low-risk breast cancer patients. In the same patients, we also compared miR-21 expression with the expression of its presumed target PTEN.

Methods

Both microarray and RT-qPCR techniques were used to assess miRNA expression levels in lymph node-positive and -negative human invasive ductal carcinoma tissues. Simultaneously, PTEN protein expression levels were assessed using immunohistochemistry.

Results

miR-486-5p and miR-139-5p were found to be down-regulated in patients with lymph node metastases, whereas miR-21 was found to be up-regulated in patients with a positive lymph node status. miR-21 expression levels were found to significantly correlate with tumour size (r = 0.403, p = 0.009; Spearman’s rank), whereas no relation was found between miR-21 and PTEN expression levels (Kruskal-Wallis test).

Conclusion

Down-regulation of miR-486-5p and miR-139-5p, in conjunction with up-regulation of miR-21, may represent a useful signature for the identification of high-risk breast cancer patients.
Appendix
Available only for authorised users
Literature
1.
2.
B. Weigelt, F.C. Geyer, J.S. Reis-Filho, Histological types of breast cancer: how special are they? Mol Oncol 4, 192–208 (2010)PubMedCrossRef
3.
N.J. Bundred, Prognostic and predictive factors in breast cancer. Cancer Treatment Reviews 27, 137–142 (2001)PubMedCrossRef
4.
G. Cheng, S. Kurita, D.A. Torigian, A. Alavi, Current status of sentinel lymph-node biopsy in patients with breast cancer. Eur J Nucl Med Mol Imaging 38, 562–575 (2011)PubMedCrossRef
5.
A. Goldhirsch, J.N. Ingle, R.D. Gelber, A.S. Coates, B. Thurlimann, H.J. Senn, Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009. Ann Oncol 20, 1319–1329 (2009)PubMedCentralPubMedCrossRef
6.
J. Krol, I. Loedige, W. Filipowicz, The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet 11, 597–610 (2010)PubMed
7.
I.A. Asangani, S.A. Rasheed, D.A. Nikolova, J.H. Leupold, N.H. Colburn, S. Post, H. Allgayer, MicroRNA-21 (miR-21) post-transcriptionally downregulates tumour suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene 27, 2128–2136 (2008)PubMedCrossRef
8.
H.K. Oh, A.L. Tan, K. Das, C.H. Ooi, N.T. Deng, I.B. Tan, E. Beillard, J. Lee, K. Ramnarayanan, S.Y. Rha, N. Palanisamy, P.M. Voorhoeve, P. Tan, Genomic loss of miR-486 regulates tumour progression and the OLFM4 antiapoptotic factor in gastric cancer. Clin Cancer Res 17, 2657–2667 (2011)PubMedCrossRef
9.
Z. Lu, M. Liu, V. Stribinskis, C.M. Klinge, K.S. Ramos, N.H. Colburn, Y. Li, MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene. Oncogene 27, 4373–4379 (2008)PubMedCrossRef
10.
R. Nagadia, P. Pandit, W.B. Coman, J. Cooper-White, C. Punyadeera, miRNAs in head and neck cancer revisited. Cell Oncol 36, 1–7 (2013)CrossRef
11.
M.V. Iorio, M. Ferracin, C.G. Liu, A. Veronese, R. Spizzo, S. Sabbioni, E. Magri, M. Pedriali, M. Fabbri, M. Campiglio, S. Menard, J.P. Palazzo, A. Rosenberg, P. Musiani, S. Volinia, I. Nenci, G.A. Calin, P. Querzoli, M. Negrini, C.M. Croce, MicroRNA gene expression deregulation in human breast cancer. Cancer Res 65, 7065–7070 (2005)PubMedCrossRef
12.
A. Aigner, MicroRNAs (miRNAs) in cancer invasion and metastasis: therapeutic approaches based on metastasis-related miRNAs. J Mol Med (Berl) 89, 445–457 (2011)CrossRef
13.
M.D. Mattie, C.C. Benz, J. Bowers, K. Sensinger, L. Wong, G.K. Scott, V. Fedele, D. Ginzinger, R. Getts, C. Haqq, Optimized high-throughput microRNA expression profiling provides novel biomarker assessment of clinical prostate and breast cancer biopsies. Mol Cancer 5, 24 (2006)PubMedCentralPubMedCrossRef
14.
A.J. Lowery, N. Miller, A. Devaney, R.E. McNeill, P.A. Davoren, C. Lemetre, V. Benes, S. Schmidt, J. Blake, G. Ball, M.J. Kerin, MicroRNA signatures predict oestrogen receptor, progesterone receptor and HER2/neu receptor status in breast cancer. Breast Cancer Res 11, R27 (2009)PubMedCentralPubMedCrossRef
15.
G.L. Huang, X.H. Zhang, G.L. Guo, K.T. Huang, K.Y. Yang, X. Shen, J. You, X.Q. Hu, Clinical significance of miR-21 expression in breast cancer: SYBR-Green I-based real-time RT-PCR study of invasive ductal carcinoma. Oncol Rep 21, 673–679 (2009)PubMed
16.
S. Zhu, H. Wu, F. Wu, D. Nie, S. Sheng, Y.Y. Mo, MicroRNA-21 targets tumour suppressor genes in invasion and metastasis. Cell Res 18, 350–359 (2008)PubMedCrossRef
17.
L.X. Yan, Q.N. Wu, Y. Zhang, Y.Y. Li, D.Z. Liao, J.H. Hou, J. Fu, M.S. Zeng, J.P. Yun, Q.L. Wu, Y.X. Zeng, J.Y. Shao, Knockdown of miR-21 in human breast cancer cell lines inhibits proliferation, in vitro migration and in vivo tumour growth. Breast Cancer Res 13, R2 (2011)PubMedCentralPubMedCrossRef
18.
L.X. Yan, X.F. Huang, Q. Shao, M.Y. Huang, L. Deng, Q.L. Wu, Y.X. Zeng, J.Y. Shao, MicroRNA miR-21 overexpression in human breast cancer is associated with advanced clinical stage, lymph node metastasis and patient poor prognosis. RNA 14, 2348–2360 (2008)PubMedCentralPubMedCrossRef
19.
B. Qian, D. Katsaros, L. Lu, M. Preti, A. Durando, R. Arisio, L. Mu, H. Yu, High miR-21 expression in breast cancer associated with poor disease-free survival in early stage disease and high TGF-beta1. Breast Cancer Res Treat 117, 131–140 (2009)PubMedCrossRef
20.
F. Meng, R. Henson, H. Wehbe-Janek, K. Ghoshal, S.T. Jacob, T. Patel, MicroRNA-21 regulates expression of the PTEN tumour suppressor gene in human hepatocellular cancer. Gastroenterology 133, 647–658 (2007)PubMedCrossRef
21.
L. Salmena, A. Carracedo, P.P. Pandolfi, Tenets of PTEN tumour suppression. Cell 133, 403–414 (2008)PubMedCrossRef
22.
S. Zhu, M.L. Si, H. Wu, Y.Y. Mo, MicroRNA-21 targets the tumour suppressor gene tropomyosin 1 (TPM1). J Biol Chem 282, 14328–14336 (2007)PubMedCrossRef
23.
L. Rask, M. Fregil, E. Hogdall, C. Mitchelmore, J. Eriksen, Development of a metastatic fluorescent Lewis Lung carcinoma mouse model: identification of mRNAs and microRNAs involved in tumour invasion. Gene 517, 72–81 (2013)PubMedCrossRef
24.
R. Sokilde, B. Kaczkowski, A. Podolska, S. Cirera, J. Gorodkin, S. Moller, T. Litman, Global microRNA analysis of the NCI-60 cancer cell panel. Mol Cancer Ther 10, 375–384 (2011)PubMedCrossRef
25.
26.
A.I. Saeed, N.K. Bhagabati, J.C. Braisted, W. Liang, V. Sharov, E.A. Howe, J. Li, M. Thiagarajan, J.A. White, J. Quackenbush, TM4 microarray software suite. Methods Enzymol 411, 134–193 (2006)PubMedCrossRef
27.
A. Perren, L.P. Weng, A.H. Boag, U. Ziebold, K. Thakore, P.L. Dahia, P. Komminoth, J.A. Lees, L.M. Mulligan, G.L. Mutter, C. Eng, Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast. Am J Pathol 155, 1253–1260 (1999)PubMedCentralPubMedCrossRef
28.
S.F. Tavazoie, C. Alarcon, T. Oskarsson, D. Padua, Q. Wang, P.D. Bos, W.L. Gerald, J. Massague, Endogenous human microRNAs that suppress breast cancer metastasis. Nature 451, 147–152 (2008)PubMedCentralPubMedCrossRef
29.
W. Li, B. Zhao, Y. Jin, K. Ruan, Development of a low-cost detection method for miRNA microarray. Acta Biochim Biophys Sin (Shanghai) 42, 296–301 (2010)CrossRef
30.
C. Chen, D.A. Ridzon, A.J. Broomer, Z. Zhou, D.H. Lee, J.T. Nguyen, M. Barbisin, N.L. Xu, V.R. Mahuvakar, M.R. Andersen, K.Q. Lao, K.J. Livak, K.J. Guegler, Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res 33, e179 (2005)PubMedCentralPubMedCrossRef
31.
P.N. D’Andrade, S. Fulmer-Smentek, Agilent MicroRNA Microarray Profiling System. Methods Mol Biol 822, 85–102 (2012)PubMedCrossRef
32.
J.M. Lee, Y. Jung, Two-Temperature Hybridization for Microarray Detection of Label-Free MicroRNAs with Attomole Detection and Superior Specificity. Angew Chem Int Ed Engl 50, 12487–12490 (2011)PubMedCrossRef
33.
S. Tam, B. R. de, M. S. Tsao and J. D. McPherson, Robust global microRNA expression profiling using next-generation sequencing technologies. Lab Invest 94, 350–358 (2014)PubMedCrossRef
34.
Y. Nakamura, H. Yasuoka, M. Tsujimoto, S. Imabun, M. Nakahara, K. Nakao, M. Nakamura, I. Mori, K. Kakudo, Lymph vessel density correlates with nodal status, VEGF-C expression, and prognosis in breast cancer. Breast Cancer Res Treat 91, 125–132 (2005)PubMedCrossRef
35.
R. Heimann, D. Ferguson, S. Gray, S. Hellman, Assessment of intratumoural vascularization (angiogenesis) in breast cancer prognosis. Breast Cancer Res Treat 52, 147–158 (1998)PubMedCrossRef
36.
37.
S. Eccles, L. Paon, J. Sleeman, Lymphatic metastasis in breast cancer: importance and new insights into cellular and molecular mechanisms. Clin Exp Metastasis 24, 619–636 (2007)PubMedCrossRef
38.
A. Smeets, A. Daemen, B. Vanden, I, O. Gevaert, B. Claes, H. Wildiers, R. Drijkoningen, H. P. Van, D. Lambrechts, M. B. De, P. Neven, C. Sotiriou, T. Vandorpe, R. Paridaens and M. R. Christiaens, Prediction of lymph node involvement in breast cancer from primary tumour tissue using gene expression profiling and miRNAs. Breast Cancer Res Treat 129, 767–776 (2011)PubMedCrossRef
39.
R. Baffa, M. Fassan, S. Volinia, B. O’Hara, C.G. Liu, J.P. Palazzo, M. Gardiman, M. Rugge, L.G. Gomella, C.M. Croce, A. Rosenberg, MicroRNA expression profiling of human metastatic cancers identifies cancer gene targets. J Pathol 219, 214–221 (2009)PubMedCrossRef
40.
R. Navon, H. Wang, I. Steinfeld, A. Tsalenko, A. Ben-Dor, Z. Yakhini, Novel rank-based statistical methods reveal microRNAs with differential expression in multiple cancer types. PLoS ONE 4, e8003 (2009)PubMedCentralPubMedCrossRef
41.
L. Yu, N.W. Todd, L. Xing, Y. Xie, H. Zhang, Z. Liu, H. Fang, J. Zhang, R.L. Katz, F. Jiang, Early detection of lung adenocarcinoma in sputum by a panel of microRNA markers. Int J Cancer 127, 2870–2878 (2010)PubMedCentralPubMedCrossRef
42.
S. Koshida, D. Kobayashi, R. Moriai, N. Tsuji, N. Watanabe, Specific overexpression of OLFM4(GW112/HGC-1) mRNA in colon, breast and lung cancer tissues detected using quantitative analysis. Cancer Sci 98, 315–320 (2007)PubMedCrossRef
43.
S.T. Mees, W.A. Mardin, S. Sielker, E. Willscher, N. Senninger, C. Schleicher, M. Colombo-Benkmann, J. Haier, Involvement of CD40 targeting miR-224 and miR-486 on the progression of pancreatic ductal adenocarcinomas. Ann Surg Oncol 16, 2339–2350 (2009)PubMedCrossRef
44.
45.
S. Corbetta, V. Vaira, V. Guarnieri, A. Scillitani, C. Eller-Vainicher, S. Ferrero, L. Vicentini, I. Chiodini, M. Bisceglia, P. Beck-Peccoz, S. Bosari, A. Spada, Differential expression of microRNAs in human parathyroid carcinomas compared with normal parathyroid tissue. Endocr Relat Cancer 17, 135–146 (2010)PubMedCrossRef
46.
Y. Ma, P. Zhang, J. Yang, Z. Liu, Z. Yang, H. Qin, Candidate microRNA biomarkers in human colorectal cancer: systematic review profiling studies and experimental validation. Int J Cancer 130, 2077–2087 (2012)PubMedCrossRef
47.
T.S. Wong, X.B. Liu, B.Y. Wong, R.W. Ng, A.P. Yuen, W.I. Wei, Mature miR-184 as Potential Oncogenic microRNA of Squamous Cell Carcinoma of Tongue. Clin Cancer Res 14, 2588–2592 (2008)PubMedCrossRef
48.
C.C. Wong, C.M. Wong, E.K. Tung, S.L. Au, J.M. Lee, R.T. Poon, K. Man, I.O. Ng, The microRNA miR-139 suppresses metastasis and progression of hepatocellular carcinoma by down-regulating Rho-kinase 2. Gastroenterology 140, 322–331 (2011)PubMedCrossRef
49.
R.L. Skalsky, B.R. Cullen, Reduced expression of brain-enriched microRNAs in glioblastomas permits targeted regulation of a cell death gene. PLoS ONE 6, e24248 (2011)PubMedCentralPubMedCrossRef
50.
C. Mascaux, J.F. Laes, G. Anthoine, A. Haller, V. Ninane, A. Burny, J.P. Sculier, Evolution of microRNA expression during human bronchial squamous carcinogenesis. Eur Respir J 33, 352–359 (2009)PubMedCrossRef
51.
W. Bao, H.J. Fu, Q.S. Xie, L. Wang, R. Zhang, Z.Y. Guo, J. Zhao, Y.L. Meng, X.L. Ren, T. Wang, Q. Li, B.Q. Jin, L.B. Yao, R.A. Wang, D.M. Fan, S.Y. Chen, L.T. Jia, A.G. Yang, HER2 interacts with CD44 to up-regulate CXCR4 via epigenetic silencing of microRNA-139 in gastric cancer cells. Gastroenterology 141, 2076–2087 (2011)PubMedCrossRef
52.
H. Yamashita, M. Nishio, T. Toyama, H. Sugiura, Z. Zhang, S. Kobayashi, H. Iwase, Coexistence of HER2 over-expression and p53 protein accumulation is a strong prognostic molecular marker in breast cancer. Breast Cancer Res 6, R24–R30 (2004)PubMedCentralPubMedCrossRef
53.
S.U. Woo, J.W. Bae, C.H. Kim, J.B. Lee, B.W. Koo, A significant correlation between nuclear CXCR4 expression and axillary lymph node metastasis in hormonal receptor negative breast cancer. Ann Surg Oncol 15, 281–285 (2008)PubMedCrossRef
54.
L. Rask, E. Balslev, S. Jorgensen, J. Eriksen, H. Flyger, S. Moller, E. Hogdall, T. Litman, B.S. Nielsen, High expression of miR-21 in tumour stroma correlates with increased cancer cell proliferation in human breast cancer. APMIS 119, 663–673 (2011)PubMedCrossRef
55.
L.F. Sempere, M. Preis, T. Yezefski, H. Ouyang, A.A. Suriawinata, A. Silahtaroglu, J.R. Conejo-Garcia, S. Kauppinen, W. Wells, M. Korc, Fluorescence-based codetection with protein markers reveals distinct cellular compartments for altered MicroRNA expression in solid tumours. Clin Cancer Res 16, 4246–4255 (2010)PubMedCentralPubMedCrossRef
56.
R. Kalluri, M. Zeisberg, Fibroblasts in cancer. Nat Rev Cancer 6, 392–401 (2006)CrossRef
57.
Q. Yao, S. Cao, C. Li, A. Mengesha, B. Kong, M. Wei, Micro-RNA-21 regulates TGF-beta-induced myofibroblast differentiation by targeting PDCD4 in tumour-stroma interaction. Int J Cancer 128, 1783–1792 (2011)PubMedCrossRef
58.
R. Madhyastha, H. Madhyastha, Y. Nakajima, S. Omura, M. Maruyama, MicroRNA signature in diabetic wound healing: promotive role of miR-21 in fibroblast migration. Int Wound J 9, 355–361 (2012)PubMedCrossRef
59.
L. Qi, J. Bart, L.P. Tan, I. Platteel, T. Sluis, S. Huitema, G. Harms, L. Fu, H. Hollema, A. Berg, Expression of miR-21 and its targets (PTEN, PDCD4, TM1) in flat epithelial atypia of the breast in relation to ductal carcinoma in situ and invasive carcinoma. BMC Cancer 9, 163 (2009)PubMedCentralPubMedCrossRef
60.
M.S. Alexander, J.C. Casar, N. Motohashi, J.A. Myers, I. Eisenberg, R.T. Gonzalez, E.A. Estrella, P.B. Kang, G. Kawahara, L.M. Kunkel, Regulation of DMD pathology by an ankyrin-encoded miRNA. Skelet Muscle 1, 27 (2011)PubMedCentralPubMedCrossRef
Metadata
Title
Differential expression of miR-139, miR-486 and miR-21 in breast cancer patients sub-classified according to lymph node status
Authors
Lene Rask
Eva Balslev
Rolf Søkilde
Estrid Høgdall
Henrik Flyger
Jens Eriksen
Thomas Litman
Publication date
01-06-2014
Publisher
Springer Netherlands
Published in
Cellular Oncology / Issue 3/2014
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI
https://doi.org/10.1007/s13402-014-0176-6

Other articles of this Issue 3/2014

Cellular Oncology 3/2014 Go to the issue

ISCO 2014

The cancer genome: from structure to function

Original Paper

Automated classification of oral premalignant lesions using image cytometry and Random Forests-based algorithms

Original Paper

Expression of H1.5 and PLZF in granulosa cell tumors and normal ovarian tissues: a short report

Original Paper

Identification of GPM6A and GPM6B as potential new human lymphoid leukemia-associated oncogenes

Original Paper

Retinoblastoma (RB1) pocket domain mutations and promoter hyper-methylation in head and neck cancer

Review

Targeting epigenetic mechanisms and microRNAs by aspirin and other non steroidal anti-inflammatory agents - implications for cancer treatment and chemoprevention
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits