Inhibition of the Autocrine IL-6-JAK2-STAT3-calprotectin Axis as Targeted Therapy for HR-/HER2+ Breast Cancers

Genes Dev. 2015 Aug 1;29(15):1631-48. doi: 10.1101/gad.262642.115. Epub 2015 Jul 30.

Abstract

HER2-positive (HER2(+)) breast adenocarcinomas are a heterogeneous group in which hormone receptor (HR) status influences therapeutic decisions and patient outcome. By combining genome-wide RNAi screens with regulatory network analysis, we identified STAT3 as a critically activated master regulator of HR(-)/HER2(+) tumors, eliciting tumor dependency in these cells. Mechanistically, HR(-)/HER2(+) cells secrete high levels of the interleukin-6 (IL-6) cytokine, inducing the activation of STAT3, which in turn promotes a second autocrine stimulus to increase S100A8/9 complex (calprotectin) production and secretion. Increased calprotectin levels activate signaling pathways involved in proliferation and resistance. Importantly, we demonstrated that inhibition of the IL-6-Janus kinase 2 (JAK2)-STAT3-calprotectin axis with FDA-approved drugs, alone and in combination with HER2 inhibitors, reduced the tumorigenicity of HR(-)/HER2(+) breast cancers, opening novel targeted therapeutic opportunities.

Keywords: HER2; STAT3; breast cancer; genetic screen; tailored therapies.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antineoplastic Agents / pharmacology
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / physiopathology*
  • Carcinogenesis / genetics
  • Cell Line, Tumor
  • Cell Survival / genetics
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Genome-Wide Association Study
  • Heterografts
  • Humans
  • Interleukin-6 / metabolism
  • Janus Kinase 2 / metabolism
  • Mice
  • Mice, SCID
  • Quinolines / pharmacology
  • Quinolones
  • RNA Interference
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*

Substances

  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Interleukin-6
  • Quinolines
  • Quinolones
  • STAT3 Transcription Factor
  • tasquinimod
  • Janus Kinase 2
  • tocilizumab