High TWIST1 mRNA expression is associated with poor prognosis in lymph node-negative and estrogen receptor-positive human breast cancer and is co-expressed with stromal as well as ECM related genes

Breast Cancer Research

John WM Martens¹  John A Foekens¹  Marcel Smid¹  Mieke A Timmermans¹  Maxime P Look¹  Anieta M Sieuwerts¹  Muhammad Riaz¹ 

[1] Erasmus University Medical Center - Daniel den Hoed Cancer Center, Department of Medical Oncology and Cancer Genomics Center, Rotterdam, The Netherlands

关键词: Stroma;    Metastasis-free survival;    Estrogen receptor;    Nodal status;    Prognosis;    mRNA expression;    Breast cancer;    TWIST1;   

Others  :  795723
DOI  :  10.1186/bcr3317

 received in 2012-03-15, accepted in 2012-09-11,  发布年份 2012

【 摘 要 】

Introduction

The TWIST homolog 1 (TWIST1) is a transcription factor that induces epithelial to mesenchymal transition (EMT), a key process in metastasis. The purpose of this study was to investigate whether TWIST1 expression predicts disease progression in a large breast cancer cohort with long-term clinical follow-up, and to reveal the biology related to TWIST1 mediated disease progression.

Methods

TWIST1 mRNA expression level was analyzed by quantitative real-time reverse polymerase chain reaction (RT-PCR) in 1,427 primary breast cancers. In uni- and multivariate analysis using Cox regression, TWIST1 mRNA expression level was associated with metastasis-free survival (MFS), disease-free survival (DFS) and overall survival (OS). Separate analyses in lymph node-negative patients (LNN, n = 778) who did not receive adjuvant systemic therapy, before and after stratification into estrogen receptor (ER)-positive (n = 552) and ER-negative (n = 226) disease, were also performed. The association of TWIST1 mRNA with survival endpoints was assessed using Kaplan-Meier analysis. Using gene expression arrays, genes showing a significant Spearman rank correlation with TWIST1 were used to identify overrepresented Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG)-annotated biological pathways.

Results

Increased mRNA expression level of TWIST1 analyzed as a continuous variable in both uni- and multivariate analysis was associated with shorter MFS in all patients (hazard ratio (HR): 1.17, 95% confidence interval, (95% CI):1.09 to 1.26; and HR: 1.17, 95% CI: 1.08 to 1.26; respectively), in LNN patients (HR: 1.22, 95% CI: 1.09 to 1.36; and HR: 1.21, 95% CI: 1.07 to 1.36; respectively) and in the ER-positive subgroup of LNN patients (HR: 1.34, 95% CI: 1.17 to 1.53; and HR: 1.32, 95% CI: 1.14 to 1.53; respectively). Similarly, high TWIST1 expression was associated with shorter DFS and OS in all patients and in the LNN/ER-positive subgroup. In contrast, no association of TWIST1 mRNA expression with MFS, DFS or OS was observed in ER-negative patients. Genes highly correlated with TWIST1 were significantly enriched for cell adhesion and ECM-related signaling pathways. Furthermore, TWIST1 mRNA was highly expressed in tumor stroma and positively related to tumor stromal content (P <0.001).

Conclusions

TWIST1 mRNA expression is an independent prognostic factor for poor prognosis in LNN/ER-positive breast cancer. The biological associations suggest an involvement of the tumor microenvironment in TWIST1's adverse role in breast cancer.

【 授权许可】

   
2012 Riaz et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin 2011, 61:69-90.
• [2]Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell 2011, 144:646-674.
• [3]Firulli AB, Conway SJ: Phosphoregulation of Twist1 provides a mechanism of cell fate control. Curr Med Chem 2008, 15:2641-2647.
• [4]Thisse B, el Messal M, Perrin-Schmitt F: The twist gene: isolation of a Drosophila zygotic gene necessary for the establishment of dorsoventral pattern. Nucleic Acids Res 1987, 15:3439-3453.
• [5]Leptin M: Twist and snail as positive and negative regulators during Drosophila mesoderm development. Genes Dev 1991, 5:1568-1576.
• [6]Kress W, Schropp C, Lieb G, Petersen B, Busse-Ratzka M, Kunz J, Reinhart E, Schafer WD, Sold J, Hoppe F, Pahnke J, Trusen A, Sörensen N, Krauss J, Collmann H: Saethre-Chotzen syndrome caused by TWIST 1 gene mutations: functional differentiation from Muenke coronal synostosis syndrome. Eur J Hum Genet 2006, 14:39-48.
• [7]Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA: Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 2004, 117:927-939.
• [8]Yang MH, Hsu DS, Wang HW, Wang HJ, Lan HY, Yang WH, Huang CH, Kao SY, Tzeng CH, Tai SK, Chang SY, Lee OK, Wu KJ: Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition. Nat Cell Biol 2010, 12:982-992.
• [9]Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA: The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008, 133:704-715.
• [10]Yu JX, Sieuwerts AM, Zhang Y, Martens JW, Smid M, Klijn JG, Wang Y, Foekens JA: Pathway analysis of gene signatures predicting metastasis of node-negative primary breast cancer. BMC Cancer 2007, 7:182. BioMed Central Full Text
• [11]Wang Y, Klijn JG, Zhang Y, Sieuwerts AM, Look MP, Yang F, Talantov D, Timmermans M, Meijer-van Gelder ME, Yu J, Jatkoe T, Berns EM, Atkins D, Foekens JA: Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 2005, 365:671-679.
• [12]Code of Conduct of the Federation of Medical Scientific Societies in the Netherlands [http://www.federa.org/?s=1&m=99] webcite In Dutch
• [13]McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM, Statistics Subcommittee of NCI-EORTC Working Group on Cancer Diagnostics: REporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat 2006, 100:229-235.
• [14]Altman DG, McShane LM, Sauerbrei W, Taube SE: Reporting recommendations for tumor marker prognostic studies (REMARK): explanation and elaboration. BMC Med 2012, 10:51. BioMed Central Full Text
• [15]Sieuwerts AM, Meijer-van Gelder ME, Timmermans M, Trapman AM, Garcia RR, Arnold M, Goedheer AJ, Portengen H, Klijn JG, Foekens JA: How ADAM-9 and ADAM-11 differentially from estrogen receptor predict response to tamoxifen treatment in patients with recurrent breast cancer: a retrospective study. Clin Cancer Res 2005, 11:7311-7321.
• [16]Sieuwerts AM, Usher PA, Meijer-van Gelder ME, Timmermans M, Martens JW, Brunner N, Klijn JG, Offenberg H, Foekens JA: Concentrations of TIMP1 mRNA splice variants and TIMP-1 protein are differentially associated with prognosis in primary breast cancer. Clin Chem 2007, 53:1280-1288.
• [17]van Agthoven T, Sieuwerts AM, Meijer-van Gelder ME, Look MP, Smid M, Veldscholte J, Sleijfer S, Foekens JA, Dorssers LC: Relevance of breast cancer antiestrogen resistance genes in human breast cancer progression and tamoxifen resistance. J Clin Oncol 2009, 27:542-549.
• [18]Foekens JA, Peters HA, Look MP, Portengen H, Schmitt M, Kramer MD, Brunner N, Janicke F, Meijer-van Gelder ME, Henzen-Logmans SC, van Putten WL, Klijn JG: The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients. Cancer Res 2000, 60:636-643.
• [19]Sieuwerts AM, Look MP, Meijer-van Gelder ME, Timmermans M, Trapman AM, Garcia RR, Arnold M, Goedheer AJ, de Weerd V, Portengen H, Klijn JG, Foekens JA: Which cyclin E prevails as prognostic marker for breast cancer? Results from a retrospective study involving 635 lymph node-negative breast cancer patients. Clin Cancer Res 2006, 12:3319-3328.
• [20]Umar A, Dalebout JC, Timmermans AM, Foekens JA, Luider TM: Method optimisation for peptide profiling of microdissected breast carcinoma tissue by matrix-assisted laser desorption/ionisation-time of flight and matrix-assisted laser desorption/ionisation-time of flight/time of flight-mass spectrometry. Proteomics 2005, 5:2680-2688.
• [21]van Nes JG, de Kruijf EM, Putter H, Faratian D, Munro A, Campbell F, Smit VT, Liefers GJ, Kuppen PJ, van de Velde CJ, Bartlett JM: Co-expression of SNAIL and TWIST determines prognosis in estrogen receptor-positive early breast cancer patients. Breast Cancer Res Treat 2012, 133:49-59.
• [22]Smid M, Wang Y, Zhang Y, Sieuwerts AM, Yu J, Klijn JG, Foekens JA, Martens JW: Subtypes of breast cancer show preferential site of relapse. Cancer Res 2008, 68:3108-3114.
• [23]Benjamini Y, Hochberg Y: Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy Stat Soc Series B = Methodological 1995, 57:289-300.
• [24]Tong W, Cao X, Harris S, Sun H, Fang H, Fuscoe J, Harris A, Hong H, Xie Q, Perkins R, Shi L, Casciano D: ArrayTrack--supporting toxicogenomic research at the U.S. Food and Drug Administration National Center for Toxicological Research. Environ Health Perspect 2003, 111:1819-1826.
• [25]ArrayTrack™ -- a microarray database, data analysis & interpretation tool [http://www.fda.gov/ScienceResearch/BioinformaticsTools/Arraytrack/default.htm] webcite
• [26]Valsesia-Wittmann S, Magdeleine M, Dupasquier S, Garin E, Jallas AC, Combaret V, Krause A, Leissner P, Puisieux A: Oncogenic cooperation between H-Twist and N-Myc overrides failsafe programs in cancer cells. Cancer Cell 2004, 6:625-630.
• [27]Fondrevelle ME, Kantelip B, Reiter RE, Chopin DK, Thiery JP, Monnien F, Bittard H, Wallerand H: The expression of Twist has an impact on survival in human bladder cancer and is influenced by the smoking status. Urol Oncol 2009, 27:268-276.
• [28]Elias MC, Tozer KR, Silber JR, Mikheeva S, Deng M, Morrison RS, Manning TC, Silbergeld DL, Glackin CA, Reh TA, Rostomily RC: TWIST is expressed in human gliomas and promotes invasion. Neoplasia 2005, 7:824-837.
• [29]Ru GQ, Wang HJ, Xu WJ, Zhao ZS: Upregulation of Twist in gastric carcinoma associated with tumor invasion and poor prognosis. Pathol Oncol Res 2011, 17:341-347.
• [30]Lee KW, Kim JH, Han S, Sung CO, Do IG, Ko YH, Um SH, Kim SH: Twist1 Is an independent prognostic factor of esophageal squamous cell carcinoma and associated with its epithelial-mesenchymal transition. Ann Surg Oncol 2012, 19:326-335.
• [31]Okada T, Suehiro Y, Ueno K, Mitomori S, Kaneko S, Nishioka M, Okayama N, Sakai K, Higaki S, Hazama S, Hirata H, Sakaida I, Oka M, Hinoda Y: TWIST1 hypermethylation is observed frequently in colorectal tumors and its overexpression is associated with unfavorable outcomes in patients with colorectal cancer. Genes Chromosomes Cancer 2010, 49:452-462.
• [32]Gomez I, Pena C, Herrera M, Munoz C, Larriba MJ, Garcia V, Dominguez G, Silva J, Rodriguez R, Garcia de Herreros A, Bonilla F, Garcia JM: TWIST1 is expressed in colorectal carcinomas and predicts patient survival. PloS One 2011, 6:e18023.
• [33]Cosset E, Hamdan G, Jeanpierre S, Voeltzel T, Sagorny K, Hayette S, Mahon FX, Dumontet C, Puisieux A, Nicolini FE, Maguer-Satta V: Deregulation of TWIST-1 in the CD34+ compartment represents a novel prognostic factor in chronic myeloid leukemia. Blood 2011, 117:1673-1676.
• [34]Valdes-Mora F, Gomez del Pulgar T, Bandres E, Cejas P, Ramirez de Molina A, Perez-Palacios R, Gallego-Ortega D, Garcia-Cabezas MA, Casado E, Larrauri J, Nistal M, González-Barón M, García-Foncillas J, Lacal JC: TWIST1 overexpression is associated with nodal invasion and male sex in primary colorectal cancer. Ann Surg Oncol 2009, 16:78-87.
• [35]Bergamaschi A, Tagliabue E, Sorlie T, Naume B, Triulzi T, Orlandi R, Russnes HG, Nesland JM, Tammi R, Auvinen P, Kosma VM, Ménard S, Børresen-Dale AL: Extracellular matrix signature identifies breast cancer subgroups with different clinical outcome. J Pathol 2008, 214:357-367.
• [36]Roman-Perez E, Casbas-Hernandez P, Pirone JR, Rein J, Carey LA, Lubet RA, Mani SA, Amos KD, Troester MA: Gene expression in extratumoral microenvironment predicts clinical outcome in breast cancer patients. Breast Cancer Res 2012, 14:R51. BioMed Central Full Text
• [37]Soini Y, Tuhkanen H, Sironen R, Virtanen I, Kataja V, Auvinen P, Mannermaa A, Kosma VM: Transcription factors zeb1, twist and snai1 in breast carcinoma. BMC Cancer 2011, 11:73. BioMed Central Full Text
• [38]Blick T, Widodo E, Hugo H, Waltham M, Lenburg ME, Neve RM, Thompson EW: Epithelial mesenchymal transition traits in human breast cancer cell lines. Clin Exp Metastasis 2008, 25:629-642.
• [39]Farmer P, Bonnefoi H, Anderle P, Cameron D, Wirapati P, Becette V, Andre S, Piccart M, Campone M, Brain E, Macgrogan G, Petit T, Jassem J, Bibeau F, Blot E, Bogaerts J, Aguet M, Bergh J, Iggo R, Delorenzi M: A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nat Med 2009, 15:68-74.