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Mitochondrial retrograde signaling induces epithelial-mesenchymal transition and generates breast cancer stem cells

M Guha1, S Srinivasan1, G Ruthel2

  • 1Department of Animal Biology and Marie Lowe Center for Comparative Oncology, School of Veterinary Medicine, Philadelphia, PA, USA.

Oncogene
|November 5, 2013
PubMed

Insights

Reducing mitochondrial DNA (mtDNA) in breast cells triggers a signaling pathway, causing epithelial-to-mesenchymal transition (EMT) and generating cancer stem cells. This discovery offers new therapeutic targets for metastatic breast cancer.

Area of Science:

  • Cell Biology
  • Cancer Research
  • Mitochondrial Biology

Background:

  • Metastatic breast tumors exhibit epithelial-to-mesenchymal transition (EMT), leading to therapy resistance.
  • The connection between reduced mitochondrial DNA (mtDNA) and EMT in breast cancer is not well understood.

Purpose of the Study:

  • To investigate the mechanistic link between mtDNA reduction and EMT in human mammary epithelial cells (hMECs).
  • To explore the role of mitochondrial retrograde signaling in mediating EMT and cancer stem cell generation.

Main Methods:

  • Reduced mtDNA content in hMECs.
  • Analysis of Calcineurin (Cn)-dependent mitochondrial retrograde signaling.
  • Assessment of EMT markers, cell morphology, polarity, and migratory/invasive phenotypes.
  • Evaluation of cancer stem cell generation.
  • Genetic manipulation including CnAα mRNA knockdown and mtDNA restoration.

Main Results:

  • mtDNA reduction activated the Calcineurin (Cn)-dependent mitochondrial retrograde signaling pathway.
  • This activation induced EMT-like changes, including fibroblastic morphology, loss of polarity, and increased invasiveness.
  • mtDNA reduction also generated breast cancer stem cells.
  • These changes were reversed by restoring mtDNA or inhibiting CnAα, confirming the causal role of retrograde signaling.

Conclusions:

  • mtDNA reduction is a novel mechanism that drives EMT and cancer stem cell formation in hMECs via mitochondrial retrograde signaling.
  • Targeting the mitochondrial retrograde signaling pathway presents a potential therapeutic strategy for overcoming EMT and cancer stem cell-mediated resistance in metastatic breast cancer.

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