Protein kinase C α is a central signaling node and therapeutic target for breast cancer stem cells

Cancer Cell. 2013 Sep 9;24(3):347-64. doi: 10.1016/j.ccr.2013.08.005.

Abstract

The epithelial-mesenchymal transition program becomes activated during malignant progression and can enrich for cancer stem cells (CSCs). We report that inhibition of protein kinase C α (PKCα) specifically targets CSCs but has little effect on non-CSCs. The formation of CSCs from non-stem cells involves a shift from EGFR to PDGFR signaling and results in the PKCα-dependent activation of FRA1. We identified an AP-1 molecular switch in which c-FOS and FRA1 are preferentially utilized in non-CSCs and CSCs, respectively. PKCα and FRA1 expression is associated with the aggressive triple-negative breast cancers, and the depletion of FRA1 results in a mesenchymal-epithelial transition. Hence, identifying molecular features that shift between cell states can be exploited to target signaling components critical to CSCs.

Publication types

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

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Cluster Analysis
  • Epithelial-Mesenchymal Transition / genetics
  • ErbB Receptors / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Neoplastic Stem Cells / metabolism*
  • Protein Kinase C-alpha / antagonists & inhibitors
  • Protein Kinase C-alpha / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • Receptors, Platelet-Derived Growth Factor / metabolism
  • Signal Transduction* / drug effects
  • Snail Family Transcription Factors
  • Transcription Factors / metabolism
  • Twist-Related Protein 1 / metabolism

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-fos
  • Snail Family Transcription Factors
  • Transcription Factors
  • Twist-Related Protein 1
  • fos-related antigen 1
  • ErbB Receptors
  • Receptors, Platelet-Derived Growth Factor
  • Protein Kinase C-alpha
  • Extracellular Signal-Regulated MAP Kinases

Associated data

  • GEO/GSE43495