Janus Kinase 1 Plays a Critical Role in Mammary Cancer Progression

Cell Rep. 2018 Nov 20;25(8):2192-2207.e5. doi: 10.1016/j.celrep.2018.10.063.


Janus kinases (JAKs) and their downstream STAT proteins play key roles in cytokine signaling, tissue homeostasis, and cancer development. Using a breast cancer model that conditionally lacks Janus kinase 1, we show here that JAK1 is essential for IL-6-class inflammatory cytokine signaling and plays a critical role in metastatic cancer progression. JAK1 is indispensable for the oncogenic activation of STAT1, STAT3, and STAT6 in ERBB2-expressing cancer cells, suggesting that ERBB2 receptor tyrosine kinase complexes do not directly activate these STAT proteins in vivo. A genome-wide gene expression analysis revealed that JAK1 signaling has pleiotropic effects on several pathways associated with cancer progression. We established that FOS and MAP3K8 are targets of JAK1/STAT3 signaling, which promotes tumorsphere formation and cell migration. The results highlight the significance of JAK1 as a rational therapeutic target to block IL-6-class cytokines, which are master regulators of cancer-associated inflammation.

Keywords: Cre recombinase; Janus kinase 1; MAP3K8; RNA sequencing; Stat transcription factor; breast cancer; c-Fos; gene targeting; mammary neoplasms; signal transduction.

Publication types

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

MeSH terms

  • Animals
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / pathology*
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Disease Progression*
  • Epithelium / metabolism
  • Epithelium / pathology
  • Female
  • Humans
  • Janus Kinase 1 / deficiency
  • Janus Kinase 1 / metabolism*
  • Ligands
  • Mice, Knockout
  • Neoplasm Metastasis
  • Neoplasm Proteins / metabolism
  • Phosphorylation
  • Receptor, ErbB-2 / metabolism
  • STAT Transcription Factors / metabolism
  • Spheroids, Cellular / metabolism
  • Spheroids, Cellular / pathology


  • Ligands
  • Neoplasm Proteins
  • STAT Transcription Factors
  • Receptor, ErbB-2
  • Janus Kinase 1