Skip to main content
Top
Published in: Breast Cancer Research and Treatment 1/2009

01-09-2009 | Epidemiology

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

Authors: Biyun Qian, Dionyssios Katsaros, Lingeng Lu, Mario Preti, Antonio Durando, Riccardo Arisio, Lina Mu, Herbert Yu

Published in: Breast Cancer Research and Treatment | Issue 1/2009

Login to get access

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.
Literature
3.
go back to reference 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 PubMedCrossRef 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 PubMedCrossRef
4.
go back to reference 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 PubMedCrossRef 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 PubMedCrossRef
5.
go back to reference 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 PubMedCrossRef 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 PubMedCrossRef
6.
go back to reference 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):716–723PubMed 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):716–723PubMed
8.
go back to reference 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 PubMedCrossRef 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 PubMedCrossRef
9.
go back to reference 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 PubMedCrossRef 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 PubMedCrossRef
10.
11.
go back to reference 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):1696–1704PubMedCrossRef 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):1696–1704PubMedCrossRef
12.
go back to reference 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 PubMedCrossRef 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 PubMedCrossRef
13.
go back to reference 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 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.
go back to reference 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 PubMedCrossRef 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 PubMedCrossRef
16.
go back to reference 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 PubMedCrossRef 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 PubMedCrossRef
19.
go back to reference 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 PubMedCrossRef 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 PubMedCrossRef
22.
go back to reference 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-GPubMedCrossRef 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-GPubMedCrossRef
25.
go back to reference 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):3272–3282PubMedCrossRef 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):3272–3282PubMedCrossRef
26.
go back to reference 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 PubMedCrossRef 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 PubMedCrossRef
27.
go back to reference 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 PubMedCrossRef 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 PubMedCrossRef
28.
go back to reference 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 PubMedCrossRef 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 PubMedCrossRef
29.
go back to reference 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 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
33.
go back to reference Pardali K, Moustakas A (2007) Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer. Biochim Biophys Acta 1775(1):21–62PubMed Pardali K, Moustakas A (2007) Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer. Biochim Biophys Acta 1775(1):21–62PubMed
34.
go back to reference 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 PubMedCrossRef 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 PubMedCrossRef
36.
go back to reference 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 PubMedCrossRef 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 PubMedCrossRef
37.
go back to reference 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 PubMedCrossRef 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 PubMedCrossRef
38.
go back to reference 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 PubMedCrossRef 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 PubMedCrossRef
39.
go back to reference 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):907-911PubMed 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):907-911PubMed
Metadata
Title
High miR-21 expression in breast cancer associated with poor disease-free survival in early stage disease and high TGF-β1
Authors
Biyun Qian
Dionyssios Katsaros
Lingeng Lu
Mario Preti
Antonio Durando
Riccardo Arisio
Lina Mu
Herbert Yu
Publication date
01-09-2009
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 1/2009
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-008-0219-7

Other articles of this Issue 1/2009

Breast Cancer Research and Treatment 1/2009 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

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