HR+HER2- breast cancers with growth factor receptor-mediated EMT have a poor prognosis and lapatinib downregulates EMT in MCF-7 cells

Tumour Biol. 2017 Mar;39(3):1010428317695028. doi: 10.1177/1010428317695028.

Abstract

Despite an overall good prognosis, a significant proportion of patients with hormone receptor positive human epidermal growth factor receptor 2 negative breast cancers develop distant metastases. The metastatic potential of epithelial cells is known to be regulated by tumor-stromal interaction and mediated by epithelial-to-mesenchymal transition. Hormone receptor positive human epidermal growth factor receptor 2 negative tumors were used to estimate markers of epithelial-to-mesenchymal transition, and the luminal breast cancer cell line MCF-7 was used to examine the interactions between integrins and growth factor receptors in causation of epithelial-to-mesenchymal transition. A total of 140 primary tumors were sub-divided into groups enriched for the markers of epithelial-to-mesenchymal transition (snail family transcriptional repressor 2 and integrin β6) versus those with low levels. Within the epithelial-to-mesenchymal transition+ tumors, there was a positive correlation between the transcripts of integrin β6 and growth factor receptors-human epidermal growth factor receptor 2 and epidermal growth factor receptor. In tumors enriched for epithelial-to-mesenchymal transition markers, patients with tumors with the highest quartile of growth factor receptor transcripts had a shorter disease-free survival compared to patients with low growth factor receptor expression by Kaplan-Meier analysis (log rank, p = 0.03). Epithelial-to-mesenchymal transition was induced in MCF-7 cells by treatment with transforming growth factor beta 1 and confirmed by upregulation of SNAI1 and SNAI2 transcripts, increase of vimentin and integrin β6 protein, and repression of E-cadherin. Treatment of these cells with the dual-specificity tyrosine-kinase inhibitor lapatinib led to downregulation of epithelial-to-mesenchymal transition as indicated by lower levels of SNAI1 and SNAI2 transcripts, integrin αvβ6, and matrix metalloproteinase 9 protein. The results suggest that synergistic interactions between growth factor receptors and integrin β6 could mediate epithelial-to-mesenchymal transition and migration in a subset of luminal breast cancers and lapatinib might be effective in disrupting this interaction.

Keywords: Breast cancer; epithelial-to-mesenchymal transition; growth factor receptors; integrin β6; lapatinib; metastasis.

MeSH terms

  • Aged
  • Antigens, Neoplasm / biosynthesis*
  • Antigens, Neoplasm / genetics
  • Biomarkers, Tumor / biosynthesis
  • Biomarkers, Tumor / genetics
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cadherins / biosynthesis
  • Disease-Free Survival
  • Epithelial-Mesenchymal Transition / drug effects
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Integrins / biosynthesis*
  • Integrins / genetics
  • Kaplan-Meier Estimate
  • Lapatinib
  • MCF-7 Cells
  • Matrix Metalloproteinase 9 / biosynthesis
  • Matrix Metalloproteinase 9 / genetics*
  • Middle Aged
  • Quinazolines / administration & dosage
  • Receptor, ErbB-2 / genetics*
  • Snail Family Transcription Factors / biosynthesis*
  • Snail Family Transcription Factors / genetics
  • Transforming Growth Factor beta1 / administration & dosage
  • Transforming Growth Factor beta1 / genetics

Substances

  • Antigens, Neoplasm
  • Biomarkers, Tumor
  • Cadherins
  • Integrins
  • Quinazolines
  • SNAI1 protein, human
  • SNAI2 protein, human
  • Snail Family Transcription Factors
  • TGFB1 protein, human
  • Transforming Growth Factor beta1
  • integrin alphavbeta6
  • Lapatinib
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • MMP9 protein, human
  • Matrix Metalloproteinase 9