Abstract
BackgroundHighly aggressive, metastatic and therapeutically resistant triple-negative breast cancers (TNBCs) are often enriched for cancer stem cells (CSC). Cytokines within the breast tumor microenvironment (TME) influence the CSC state by regulating tumor cell differentiation programs. Two prevalent breast TME cytokines are oncostatin-M (OSM) and interferon-β (IFN-β). OSM is a member of the IL-6 family of cytokines and can drive the de-differentiation of TNBC cells to a highly aggressive CSC state. Conversely, IFN-β induces the differentiation of TNBC, resulting in the repression of CSC properties. Here, we assess how these breast TME cytokines influence CSC plasticity and clinical outcome.MethodsUsing transformed human mammary epithelial cell (HMEC) and TNBC cell models, we assessed the CSC markers and properties following exposure to OSM and/or IFN-β. CSC markers included CD24, CD44, and SNAIL; CSC properties included tumor sphere formation, migratory capacity, and tumor initiation.ResultsThere are three major findings from our study. First, exposure of purified, non-CSC to IFN-β prevents OSM-mediated CD44 and SNAIL expression and represses tumor sphere formation and migratory capacity. Second, during OSM-induced de-differentiation, OSM represses endogenous IFN-β mRNA expression and autocrine/paracrine IFN-β signaling. Restoring IFN-β signaling to OSM-driven CSC re-engages IFN-β-mediated differentiation by repressing OSM/STAT3/SMAD3-mediated SNAIL expression, tumor initiation, and growth. Finally, the therapeutic use of IFN-β to treat OSM-driven tumors significantly suppresses tumor growth.ConclusionsOur findings suggest that the levels of IFN-β and OSM in TNBC dictate the abundance of cells with a CSC phenotype. Indeed, TNBCs with elevated IFN-β signaling have repressed CSC properties and a better clinical outcome. Conversely, TNBCs with elevated OSM signaling have a worse clinical outcome. Likewise, since OSM suppresses IFN-β expression and signaling, our studies suggest that strategies to limit OSM signaling or activate IFN-β signaling will disengage the de-differentiation programs responsible for the aggressiveness of TNBCs.
Highlights
Aggressive, metastatic and therapeutically resistant triple-negative breast cancers (TNBCs) are often enriched for cancer stem cells (CSC)
The expression of IFN-stimulated genes (ISGs) following IFN-β treatment occurs concomitantly with the differentiation of Mes/CSC to a less aggressive, epithelial-like state [12, 16]. These findings were clinically validated as elevated expression of an experimentally derived IFN-β metagene signature correlated with repressed expression of CSC-related genes and improved survival outcome in TNBC patients [12]
Examination of mesenchymal markers revealed that IFN-β inhibited the OSM-mediated expression of CD44, and prevented repression of Claudin-1 and E-cadherin (Fig. 1d)
Summary
Metastatic and therapeutically resistant triple-negative breast cancers (TNBCs) are often enriched for cancer stem cells (CSC). In comparison with other subtypes, TNBC is associated with a higher risk of patient mortality over a 10-year period [1], due in part to the increased development of metastasis and resistance to therapy These malignant characteristics are attributed to self-renewing cancer stem cells (CSC), which are enriched in TNBC [2]. A recent screen of TME cytokines identified oncostatin-M (OSM), a member of the IL-6 superfamily, as a potent inducer of cancer cell de-differentiation, resulting in the acquisition of CSC markers and biological properties (including tumor-initiating capacity, metastatic outgrowth, and drug resistance [2,3,4]). We recently demonstrated that OSM-activated STAT3 cooperates with the TGF-β effector SMAD3 to drive increased mesenchymal stem cell properties [4]
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