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Open Access 01-10-2012 | Research article

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

Authors: Muhammad Riaz, Anieta M Sieuwerts, Maxime P Look, Mieke A Timmermans, Marcel Smid, John A Foekens, John WM Martens

Published in: Breast Cancer Research | Issue 5/2012

Abstract

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.

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Title: 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
Authors: Muhammad Riaz
Anieta M Sieuwerts
Maxime P Look
Mieke A Timmermans
Marcel Smid
John A Foekens
John WM Martens
Publication date: 01-10-2012
Publisher: BioMed Central
Published in: Breast Cancer Research / Issue 5/2012
Electronic ISSN: 1465-542X
DOI: https://doi.org/10.1186/bcr3317

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