Inhibition of FASN and ERα signalling during hyperglycaemia-induced matrix-specific EMT promotes breast cancer cell invasion via a caveolin-1-dependent mechanism

H. A. Zielinska*, J. M.P. Holly, A. Bahl, C. M. Perks

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

12 Citations (Scopus)
272 Downloads (Pure)

Abstract

Since disturbed metabolic conditions such as obesity and diabetes can be critical determinants of breast cancer progression and therapeutic failure, we aimed to determine the mechanism responsible for their pro-oncogenic effects. Using non-invasive, epithelial-like ERα-positive MCF-7 and T47D human breast cancer cells we found that hyperglycaemia induced epithelial to mesenchymal transition (EMT), a key programme responsible for the development of metastatic disease. This was demonstrated by loss of the epithelial marker E-cadherin together with increases in mesenchymal markers such as vimentin, fibronectin and the transcription factor SLUG, together with an enhancement of cell growth and invasion. These phenotypic changes were only observed with cells grown on fibronectin and not with those plated on collagen. Analyzing metabolic parameters, we found that hyperglycaemia-induced, matrix-specific EMT promoted the Warburg effect by upregulating glucose uptake, lactate release and specific glycolytic enzymes and transporters. We showed that silencing of fatty acid synthase (FASN) and the downstream ERα, which we showed previously to mediate hyperglycaemia-induced chemoresistance in these cells, resulted in suppression of cell growth: however, this also resulted in a dramatic enhancement of cell invasion and SLUG mRNA levels via a novel caveolin-1-dependent mechanism.

Original languageEnglish
Pages (from-to)187-202
Number of pages16
JournalCancer Letters
Volume419
Early online date10 Jan 2018
DOIs
Publication statusPublished - 10 Apr 2018

Structured keywords

  • ICEP

Keywords

  • Breast cancer
  • Epithelial to mesenchymal transition
  • Fibronectin
  • Hyperglycaemia
  • Warburg effect

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