Constitutive activation of STAT3 in breast cancer cells: A review

Int J Cancer. 2016 Jun 1;138(11):2570-8. doi: 10.1002/ijc.29923. Epub 2015 Nov 28.


Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in numerous cancer types, including more than 40% of breast cancers. In contrast to tight regulation of STAT3 as a latent transcription factor in normal cells, its signaling in breast cancer oncogenesis is multifaceted. Signaling through the IL-6/JAK/STAT3 pathway initiated by the binding of IL-6 family of cytokines (i.e., IL-6 and IL-11) to their receptors have been implicated in breast cancer development. Receptors with intrinsic kinase activity such as EGFR and VEGFR directly or indirectly induce STAT3 activation in various breast cancer types. Aberrant STAT3 signaling promotes breast tumor progression through deregulation of the expression of downstream target genes which control proliferation (Bcl-2, Bcl-xL, Survivin, Cyclin D1, c-Myc and Mcl-1), angiogenesis (Hif1α and VEGF) and epithelial-mesenchymal transition (Vimentin, TWIST, MMP-9 and MMP-7). These multiple modes of STAT3 regulation therefore make it a central linking point for a multitude of signaling processes. Extensive efforts to target STAT3 activation in breast cancer had no remarkable success in the past because the highly interconnected nature of STAT3 signaling introduces lack of selectivity in pathway identification for STAT3 targeted molecular therapies or because its role in tumorigenesis may not be as critical as it was thought. This review provides a full spectrum of STAT3's involvement in breast cancer by consolidating the knowledge about its role in breast cancer development at multiple levels: its differential regulation by different receptor signaling pathways, its downstream target genes, and modification of its transcriptional activity by its coregulatory transcription factors.

Keywords: STAT3; breast cancer; regulation; target genes; transcription factor; tumor growth.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • ErbB Receptors / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Interleukin-6 / genetics
  • Janus Kinases / genetics
  • STAT3 Transcription Factor / biosynthesis
  • STAT3 Transcription Factor / genetics*
  • Signal Transduction
  • Transcriptional Activation / genetics*
  • Vascular Endothelial Growth Factor Receptor-1 / genetics


  • IL6 protein, human
  • Interleukin-6
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • EGFR protein, human
  • ErbB Receptors
  • Vascular Endothelial Growth Factor Receptor-1
  • Janus Kinases