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Targeting an IKBKE cytokine network impairs triple-negative breast cancer growth
Thanh U. Barbie, … , David A. Barbie, William E. Gillanders
Thanh U. Barbie, … , David A. Barbie, William E. Gillanders
Published November 3, 2014
Citation Information: J Clin Invest. 2014;124(12):5411-5423. https://doi.org/10.1172/JCI75661.
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Research Article Oncology

Targeting an IKBKE cytokine network impairs triple-negative breast cancer growth

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Abstract

Triple-negative breast cancers (TNBCs) are a heterogeneous set of cancers that are defined by the absence of hormone receptor expression and HER2 amplification. Here, we found that inducible IκB kinase–related (IKK-related) kinase IKBKE expression and JAK/STAT pathway activation compose a cytokine signaling network in the immune-activated subset of TNBC. We found that treatment of cultured IKBKE-driven breast cancer cells with CYT387, a potent inhibitor of TBK1/IKBKE and JAK signaling, impairs proliferation, while inhibition of JAK alone does not. CYT387 treatment inhibited activation of both NF-κB and STAT and disrupted expression of the protumorigenic cytokines CCL5 and IL-6 in these IKBKE-driven breast cancer cells. Moreover, in 3D culture models, the addition of CCL5 and IL-6 to the media not only promoted tumor spheroid dispersal but also stimulated proliferation and migration of endothelial cells. Interruption of cytokine signaling by CYT387 in vivo impaired the growth of an IKBKE-driven TNBC cell line and patient-derived xenografts (PDXs). A combination of CYT387 therapy with a MEK inhibitor was particularly effective, abrogating tumor growth and angiogenesis in an aggressive PDX model of TNBC. Together, these findings reveal that IKBKE-associated cytokine signaling promotes tumorigenicity of immune-driven TNBC and identify a potential therapeutic strategy using clinically available compounds.

Authors

Thanh U. Barbie, Gabriela Alexe, Amir R. Aref, Shunqiang Li, Zehua Zhu, Xiuli Zhang, Yu Imamura, Tran C. Thai, Ying Huang, Michaela Bowden, John Herndon, Travis J. Cohoon, Timothy Fleming, Pablo Tamayo, Jill P. Mesirov, Shuji Ogino, Kwok-Kin Wong, Matthew J. Ellis, William C. Hahn, David A. Barbie, William E. Gillanders

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Figure 1

IKBKE overexpression defines a subset of TNBCs.

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IKBKE overexpression defines a subset of TNBCs.
(A) IKBKE amplification ...
(A) IKBKE amplification and mRNA expression in the TCGA breast cancer data set, compared with IL-1 signature enrichment by single-sample gene set enrichment analysis (ssGSEA). Light purple represents basal but progesterone receptor–positive tumors. Black lines indicate IKBKE amplification on 1q32, red indicates high expression, and blue indicates low expression. (B) Immunoblot of IKBKE and β-actin levels across a panel of TNBC cell lines compared with BT474 (HER2+), ZR-751 (luminal, IKBKE-amplified), and MCF-10A (basal-like, nontransformed) cells. (C) Relative cell viability by CellTiter-Glo (CTG) Luminescent Cell Viability Assay on day 3 or day 10 following expression of 2 different IKBKE shRNAs compared with shGFP control in ZR-751 or MDA-MB-468 cells. Values represent mean and SEM of triplicate samples. (D) Crystal violet–stained cells and immunoblots of IKBKE and β-actin levels from parallel wells following control shGFP expression or that of 2 different IKBKE-specific shRNAs in the indicated cell lines.
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