Over-Expressed Twist Associates with Markers of Epithelial Mesenchymal Transition and Predicts Poor Prognosis in Breast Cancers via ERK and Akt Activation

PLoS One. 2015 Aug 21;10(8):e0135851. doi: 10.1371/journal.pone.0135851. eCollection 2015.

Abstract

Overexpression of Twist, a highly conserved basic helix-loop-helix transcription factor, is associated with epithelial-mesenchymal transition (EMT) and predicts poor prognosis in various kinds of cancers, including breast cancer. In order to further clarify Twist's role in breast cancer, we detected Twist expression in breast cancer tissues by immunohistochemistry. Twist expression was observed in 54% (220/408) of breast cancer patients and was positively associated with tumor size, Ki67, VEGF-C and HER2 expression. Conversely, Twist was negatively associated with estrogen receptor (ER), progesterone receptor (PgR) and E-cadherin expression. Patients with Twist expression had a poorer prognosis for 30-month disease free survival (DFS) (82.9%) than patients with negative Twist (92.3%). Overexpression of Twist led to dramatic changes in cellular morphology, proliferation, migratory/invasive capability, and expression of EMT-related biomarkers in breast cancer cells. Moreover, we show that Twist serves as a driver of tumorigenesis, as well as an inducer of EMT, at least in part, through activation of the Akt and extracellular signal-regulated protein kinase (ERK) pathways which are critical for Twist-mediated EMT. Our results demonstrate that Twist expression is an important prognostic factor in breast cancer patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Cadherins / genetics
  • Cadherins / metabolism
  • Carcinoma, Ductal, Breast / diagnosis
  • Carcinoma, Ductal, Breast / genetics*
  • Carcinoma, Ductal, Breast / mortality
  • Carcinoma, Ductal, Breast / pathology
  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition / genetics*
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Ki-67 Antigen / genetics
  • Ki-67 Antigen / metabolism
  • Lymphatic Metastasis
  • Middle Aged
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Neoplasm Grading
  • Neoplasm Staging
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Prognosis
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism
  • Receptors, Progesterone / genetics
  • Receptors, Progesterone / metabolism
  • Signal Transduction
  • Survival Analysis
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Twist-Related Protein 1 / genetics*
  • Twist-Related Protein 1 / metabolism
  • Vascular Endothelial Growth Factor C / genetics
  • Vascular Endothelial Growth Factor C / metabolism

Substances

  • Biomarkers, Tumor
  • Cadherins
  • ESR1 protein, human
  • Estrogen Receptor alpha
  • Ki-67 Antigen
  • Nuclear Proteins
  • Receptors, Progesterone
  • TWIST1 protein, human
  • Tumor Suppressor Protein p53
  • Twist-Related Protein 1
  • Vascular Endothelial Growth Factor C
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 3

Grants and funding

This work was partly supported by the funds from the Major State Basic Research Development Program of China (No. 2011CB707705.http://www.973.gov.cn/English/Index.aspx); Natural Science Foundation Committee (No. 31271068, 81302331/http://www.nsfc.gov.cn/publish/portal1/); Guangdong Provincial Science and Technology Planning Project (2011B031800305/http://www.gdstc.gov.cn/eng/mission.html) and Guangdong Provincial Key Laboratory on Breast Cancer Diagnosis and Treatment Research.