TAK1 mediates microenvironment-triggered autocrine signals and promotes triple-negative breast cancer lung metastasis

Oihana Iriondo, Yarong Liu, Grace Lee, Mostafa Elhodaky, Christian Jimenez, Lin Li, Julie Lang, Pin Wang and Min Yu ()
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Oihana Iriondo: University of Southern California
Yarong Liu: University of Southern California
Grace Lee: University of Southern California
Mostafa Elhodaky: University of Southern California
Christian Jimenez: University of Southern California
Lin Li: University of Southern California
Julie Lang: University of Southern California
Pin Wang: University of Southern California
Min Yu: University of Southern California

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: Abstract Triple-negative breast cancer (TNBC) is a highly metastatic subtype of breast cancer that has limited therapeutic options. Thus, developing novel treatments for metastatic TNBC is an urgent need. Here, we show that nanoparticle-mediated delivery of transforming growth factor-β1-activated kinase-1 (TAK1) inhibitor 5Z-7-Oxozeaenol can inhibit TNBC lung metastasis in most animals tested. P38 is a central signal downstream of TAK1 in TNBC cells in TAK1-mediated response to multiple cytokines. Following co-culturing with macrophages or fibroblasts, TNBC cells express interleukin-1 (IL1) or tumor necrosis factor-α (TNFα), respectively. Compared to TAK1 inhibition, suppressing IL1 signaling with recombinant IL1 receptor antagonist (IL1RA) is less efficient in reducing lung metastasis, possibly due to the additional TAK1 signals coming from distinct stromal cells. Together, these observations suggest that TAK1 may play a central role in promoting TNBC cell adaptation to the lung microenvironment by facilitating positive feedback signaling mediated by P38. Approaches targeting the key TAK1-P38 signal could offer a novel means for suppressing TNBC lung metastasis.

Date: 2018
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DOI: 10.1038/s41467-018-04460-w

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