The cJUN NH2-terminal kinase (JNK) signaling pathway promotes genome stability and prevents tumor initiation

Elife. 2018 Jun 1:7:e36389. doi: 10.7554/eLife.36389.

Abstract

Breast cancer is the most commonly diagnosed malignancy in women. Analysis of breast cancer genomic DNA indicates frequent loss-of-function mutations in components of the cJUN NH2-terminal kinase (JNK) signaling pathway. Since JNK signaling can promote cell proliferation by activating the AP1 transcription factor, this apparent association of reduced JNK signaling with tumor development was unexpected. We examined the effect of JNK deficiency in the murine breast epithelium. Loss of JNK signaling caused genomic instability and the development of breast cancer. Moreover, JNK deficiency caused widespread early neoplasia and rapid tumor formation in a murine model of breast cancer. This tumor suppressive function was not mediated by a role of JNK in the growth of established tumors, but by a requirement of JNK to prevent tumor initiation. Together, these data identify JNK pathway defects as 'driver' mutations that promote genome instability and tumor initiation.

Keywords: JNK; breast cancer; cancer biology; cell biology; mouse; stress-activated MAPK.

Publication types

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

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Carcinogenesis / genetics*
  • Carcinogenesis / pathology*
  • Cell Proliferation
  • Cell Survival
  • Disease Models, Animal
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Exome / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genomic Instability*
  • Humans
  • JNK Mitogen-Activated Protein Kinases / deficiency
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • MAP Kinase Signaling System*
  • Mice, Inbred C57BL
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Phenotype

Substances

  • JNK Mitogen-Activated Protein Kinases