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
Cette étude (778 patientes) montre qu'un niveau d'expression intratumorale élevé de l'ARNm du gène TWIST1 est associé à un pronostic défavorable chez les patientes atteintes d'un cancer du sein ER+ sans envahissement ganglionnaire (552 cas) et est corrélé à l'expression de gènes liés au stroma et aux protéines de la matrice extracellulaire
INTRODUCTION: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 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):1.09-1.26; and HR: 1.17, 95% CI:1.08-1.26; respectively), in LNN patients (HR: 1.22, 95% CI:1.09-1.36; and HR: 1.21, 95% CI:1.07-1.36; respectively) and in the ER-positive subgroup of LNN patients (HR: 1.34, 95% CI:1.17-1.53; and HR: 1.32, 95% CI:1.14-1.53; 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 expression was 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.
Breast Cancer Research , résumé, 2011