XIAP Regulation by MNK Links MAPK and NFκB Signaling to Determine an Aggressive Breast Cancer Phenotype
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 01, 2018
- Source ID
- 10.1158/0008-5472.can-17-1667
Entities
People
- Gayathri R Devi
- Gregory M Palmer
- Herbert Levine
- Joseph Geradts
- Matthias Gromeier
- Michael A. Morse
- Michael C Brown
- Mohit Kumar Jolly
- Myron K. Evans
- Peter B. Vermeulen
- Steven J. Van Laere
- Timothy J Robinson
- Xuhui Bao
Organizations
- Cancer Prevention and Research Institute of Texas
- Duke University
- Duke University Hospital
- National Institutes of Health
- Rice University
- United States Department of Defense
- University of Antwerp