A TDO2-AhR signaling axis facilitates anoikis resistance and metastasis in triple-negative breast cancer

The ability of a cancer cell to develop resistance to anoikis, a programmed cell death process triggered by substratum detachment, is a critical step in the metastatic cascade. Triple-negative breast cancers (TNBC) exhibit higher rates of metastasis after diagnosis, relative to estrogen-positive bre...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2015-11, Vol.75 (21), p.4651-4664
Main Authors: D'Amato, Nicholas C, Rogers, Thomas J, Gordon, Michael A, Greene, Lisa I, Cochrane, Dawn R, Spoelstra, Nicole S, Nemkov, Travis G, D'Alessandro, Angelo, Hansen, Kirk C, Richer, Jennifer K
Format: Article
Language:English
Subjects:
Animals
Anoikis - physiology
Cell Line, Tumor
Cell Movement - genetics
Cell Proliferation - genetics
Gene Expression Regulation, Neoplastic - genetics
Humans
Kynurenine - metabolism
Mice
Mice, Inbred NOD
Mice, SCID
Neoplasm Invasiveness - genetics
Neoplasm Metastasis
NF-kappa B - metabolism
Receptors, Aryl Hydrocarbon - antagonists & inhibitors
Receptors, Aryl Hydrocarbon - genetics
Receptors, Aryl Hydrocarbon - metabolism
RNA Interference
RNA, Small Interfering
Signal Transduction
Triple Negative Breast Neoplasms - pathology
Tryptophan Oxygenase - antagonists & inhibitors
Tryptophan Oxygenase - genetics
Tryptophan Oxygenase - metabolism
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Summary:The ability of a cancer cell to develop resistance to anoikis, a programmed cell death process triggered by substratum detachment, is a critical step in the metastatic cascade. Triple-negative breast cancers (TNBC) exhibit higher rates of metastasis after diagnosis, relative to estrogen-positive breast cancers, but while TNBC cells are relatively more resistant to anoikis, the mechanisms involved are unclear. Through gene expression and metabolomic profiling of TNBC cells in forced suspension culture, we identified a molecular pathway critical for anchorage-independent cell survival. TNBC cells in suspension upregulated multiple genes in the kynurenine pathway of tryptophan catabolism, including the enzyme tryptophan 2,3-dioxygenase (TDO2), in an NF-κB-dependent manner. Kynurenine production mediated by TDO2 in TNBC cells was sufficient to activate aryl hydrocarbon receptor (AhR), an endogenous kynurenine receptor. Notably, pharmacologic inhibition or genetic attenuation of TDO2 or AhR increased cellular sensitivity to anoikis, and also reduced proliferation, migration, and invasion of TNBC cells. In vivo, TDO2 inhibitor-treated TNBC cells inhibited colonization of the lung, suggesting that TDO2 enhanced metastatic capacity. In clinical specimens of TNBC, elevated expression of TDO2 was associated with increased disease grade, estrogen receptor-negative status, and shorter overall survival. Our results define an NF-κB-regulated signaling axis that promotes anoikis resistance, suggest functional connections with inflammatory modulation by the kynurenine pathway, and highlight TDO2 as an attractive target for treatment of this aggressive breast cancer subtype.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-15-2011