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

Publication ,  Journal Article
Evans, MK; Brown, MC; Geradts, J; Bao, X; Robinson, TJ; Jolly, MK; Vermeulen, PB; Palmer, GM; Gromeier, M; Levine, H; Morse, MA; Van Laere, SJ ...
Published in: Cancer Res
April 1, 2018

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.

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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

April 1, 2018

Volume

78

Issue

7

Start / End Page

1726 / 1738

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • X-Linked Inhibitor of Apoptosis Protein
  • Transcriptional Activation
  • Protein Serine-Threonine Kinases
  • Oncology & Carcinogenesis
  • NF-kappa B
  • Mice, SCID
  • Mice, Nude
  • Mice
  • MAP Kinase Signaling System
 

Citation

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MLA
NLM
Evans, M. K., Brown, M. C., Geradts, J., Bao, X., Robinson, T. J., Jolly, M. K., … Devi, G. R. (2018). XIAP Regulation by MNK Links MAPK and NFκB Signaling to Determine an Aggressive Breast Cancer Phenotype. Cancer Res, 78(7), 1726–1738. https://doi.org/10.1158/0008-5472.CAN-17-1667
Evans, Myron K., Michael C. Brown, Joseph Geradts, Xuhui Bao, Timothy J. Robinson, Mohit Kumar Jolly, Peter B. Vermeulen, et al. “XIAP Regulation by MNK Links MAPK and NFκB Signaling to Determine an Aggressive Breast Cancer Phenotype.Cancer Res 78, no. 7 (April 1, 2018): 1726–38. https://doi.org/10.1158/0008-5472.CAN-17-1667.
Evans MK, Brown MC, Geradts J, Bao X, Robinson TJ, Jolly MK, et al. XIAP Regulation by MNK Links MAPK and NFκB Signaling to Determine an Aggressive Breast Cancer Phenotype. Cancer Res. 2018 Apr 1;78(7):1726–38.
Evans, Myron K., et al. “XIAP Regulation by MNK Links MAPK and NFκB Signaling to Determine an Aggressive Breast Cancer Phenotype.Cancer Res, vol. 78, no. 7, Apr. 2018, pp. 1726–38. Pubmed, doi:10.1158/0008-5472.CAN-17-1667.
Evans MK, Brown MC, Geradts J, Bao X, Robinson TJ, Jolly MK, Vermeulen PB, Palmer GM, Gromeier M, Levine H, Morse MA, Van Laere SJ, Devi GR. 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.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

April 1, 2018

Volume

78

Issue

7

Start / End Page

1726 / 1738

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • X-Linked Inhibitor of Apoptosis Protein
  • Transcriptional Activation
  • Protein Serine-Threonine Kinases
  • Oncology & Carcinogenesis
  • NF-kappa B
  • Mice, SCID
  • Mice, Nude
  • Mice
  • MAP Kinase Signaling System