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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.

breast cancer research

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