MicroRNA-30c inhibits human breast tumour chemotherapy resistance by regulating TWF1 and IL-11

Nat Commun. 2013;4:1393. doi: 10.1038/ncomms2393.

Abstract

Chemotherapy resistance frequently drives tumour progression. However, the underlying molecular mechanisms are poorly characterized. Epithelial-to-mesenchymal transition has been shown to correlate with therapy resistance, but the functional link and signalling pathways remain to be elucidated. Here we report that microRNA-30c, a human breast tumour prognostic marker, has a pivotal role in chemoresistance by a direct targeting of the actin-binding protein twinfilin 1, which promotes epithelial-to-mesenchymal transition. An interleukin-6 family member, interleukin-11 is identified as a secondary target of twinfilin 1 in the microRNA-30c signalling pathway. Expression of microRNA-30c inversely correlates with interleukin-11 expression in primary breast tumours and low interleukin-11 correlates with relapse-free survival in breast cancer patients. Our study demonstrates that microRNA-30c is transcriptionally regulated by GATA3 in breast tumours. Identification of a novel microRNA-mediated pathway that regulates chemoresistance in breast cancer will facilitate the development of novel therapeutic strategies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Biomarkers, Tumor / metabolism
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Cluster Analysis
  • Cytoskeleton / drug effects
  • Cytoskeleton / genetics
  • Doxorubicin / pharmacology
  • Doxorubicin / therapeutic use
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics*
  • Epithelial-Mesenchymal Transition / drug effects
  • Epithelial-Mesenchymal Transition / genetics
  • Female
  • GATA3 Transcription Factor / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Interleukin-11 / genetics
  • Interleukin-11 / metabolism*
  • Mice
  • MicroRNAs / metabolism*
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism*
  • Prognosis
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Suppression, Genetic / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Biomarkers, Tumor
  • GATA3 Transcription Factor
  • GATA3 protein, human
  • IL11 protein, human
  • Interleukin-11
  • MIRN30b microRNA, human
  • MicroRNAs
  • Microfilament Proteins
  • TWF1 protein, human
  • Doxorubicin
  • Protein-Tyrosine Kinases