XIAP Regulation by MNK Links MAPK and NFκB Signaling to Determine an Aggressive Breast Cancer Phenotype

Cancer Res. 2018 Apr 1;78(7):1726-1738. doi: 10.1158/0008-5472.CAN-17-1667. Epub 2018 Jan 19.


Hyperactivation of the NFκB pathway is a distinct feature of inflammatory breast cancer (IBC), a highly proliferative and lethal disease. Gene expression studies in IBC patient tissue have linked EGFR (EGFR/HER2)-mediated MAPK signaling to NFκB hyperactivity, but the mechanism(s) by which this occurs remain unclear. Here, we report that the X-linked inhibitor of apoptosis protein (XIAP) plays a central role in linking these two pathways. XIAP overexpression correlated with poor prognoses in breast cancer patients and was frequently observed in untreated IBC patient primary tumors. XIAP drove constitutive NFκB transcriptional activity, which mediated ALDH positivity (a marker of stem-like cells), in vivo tumor growth, and an IBC expression signature in patient-derived IBC cells. Using pathway inhibitors and mathematical models, we defined a new role for the MAPK interacting (Ser/Thr)-kinase (MNK) in enhancing XIAP expression and downstream NFκB signaling. Furthermore, targeted XIAP knockdown and treatment with a MNK inhibitor decreased tumor cell migration in a dorsal skin fold window chamber murine model that allowed for intravital imaging of local tumor growth and migration. Together, our results indicate a novel role for XIAP in the molecular cross-talk between MAPK and NFκB pathways in aggressive tumor growth, which has the potential to be therapeutically exploited.Significance: Signaling by the MNK kinase is essential in inflammatory breast cancer, and it can be targeted to inhibit XIAP-NFκB signaling and the aggressive phenotype of this malignancy. Cancer Res; 78(7); 1726-38. ©2018 AACR.

Publication types

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

MeSH terms

  • Aldehyde Dehydrogenase / metabolism
  • Animals
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • ErbB Receptors / metabolism
  • Female
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • MAP Kinase Signaling System
  • Mice
  • Mice, Nude
  • Mice, SCID
  • NF-kappa B / metabolism*
  • Protein Serine-Threonine Kinases / metabolism*
  • Transcriptional Activation / genetics
  • X-Linked Inhibitor of Apoptosis Protein / genetics
  • X-Linked Inhibitor of Apoptosis Protein / metabolism*
  • Xenograft Model Antitumor Assays


  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • Aldehyde Dehydrogenase
  • MKNK1 protein, human
  • EGFR protein, human
  • ErbB Receptors
  • Protein Serine-Threonine Kinases