TNF-α increases breast cancer stem-like cells through up-regulating TAZ expression via the non-canonical NF-κB pathway

Abstract

Breast cancer patients often suffer from disease relapse and metastasis due to the presence of breast cancer stem-like cells (BCSCs). Numerous studies have reported that high levels of inflammatory factors, including tumor necrosis factor alpha (TNF-α), promote BCSCs. However, the mechanism by which tnf-α promotes BCSCs is unclear. In this study, we demonstrate that TNF-α up-regulates TAZ, a transcriptional co-activator promoting BcSc self-renewal capacity in human breast cancer cell lines. Depletion of TAZ abrogated the increase in BCSCs mediated by TNF-α. TAZ is induced by TNF-α through the non-canonical nf-κB pathway, and our findings suggest that TAZ plays a crucial role in inflammatory factor-promoted breast cancer stemness and could serve as a promising therapeutic target.Breast cancer is one of the most common malignances and a serious threat to women's health worldwide 1 . Inflammation, especially chronic inflammation, plays an important role in cancer initiation and progression 2 . Tumor cells and a variety of leukocytes attracted by tumor cells produce various cytokines and chemokines that affect cancer development 3 . In general, cytokines are divided into two groups. One group comprises pro-inflammatory factors, including tumor necrosis factor alpha (TNF-α), IL1β, IL-6, etc 4,5 . The other group is made of anti-inflammatory factors, including IL-10, IL-13, etc 5 . High levels of pro-inflammatory cytokines promote tumor growth and migration, enhance the survival of malignant cells, suppress adaptive immune responses, and cause resistance to hormones and chemotherapeutic agents 6,7 . Non-steroidal anti-inflammatory drugs decrease the risk for developing and the risk of mortality in breast cancer 3 . Characterization of the mechanisms by which inflammatory cytokines promote breast cancer development may offer new therapeutic opportunities.TNF-α is a well-documented pro-inflammatory cytokine that is up-regulated in breast cancer, and high levels of TNF-α are associated with breast cancer recurrence 8,9 . Additionally, TNF-α levels are positively correlated with tumor grade in serous ovarian tumors 10 . Moreover, TNF-α knockout mice are less susceptible to DMBA-or TPA-induced skin tumors 8 . TNF-α binds to two different receptors, TNF-α receptor 1 and 2 (TNFR1/2), to activate the NF-κB signaling pathway 11,12 . TNFR1/2 activates IKK and subsequently causes IκBα phosphorylation, ubiquitination, and degradation, leading to p65, RelB or p50 translocation to the nucleus. In addition to the canonical NF-κB pathway, TNF-α is able to activate JNK, MAPKs, AKT, and the non-canonical NF-κB pathway [13][14][15] . TNF-α up-regulates over 400 inflammatory genes, including cell-adhesion molecules, anti-apoptotic proteins, inflammatory cytokines, and chemokines 16,17 .Ginalu Storci et al. reported that TNF-α increases the proportion of breast cancer stem-like cells (BCSCs) through NF-κB/HIF1α/Slug 18 . BCSCs are a small subpopulation of the primary breast tumor with differentiation and self-renewal capacities that are re...

AWP1 Restrains the Aggressive Behavior of Breast Cancer Cells Induced by TNF-α

“…Gao et al., also recently demonstrated that TNF-α mediates breast cancer cell migration through YAP signal activation, indicating the involvement of both canonical and non-canonical NF-κB signaling in this process ( 36 ). Moreover, TNF-α was reported to increase the proportion of breast cancer stem-like cells through NF-κB/HIF1α/Slug, indicative of primary breast tumors with self-renewal capacities that are resistant to cell death ( 37 ). TNF-α is also characterized by an imbalance between survival and apoptosis signals in many pathological situations, including cancer ( 38 ).…”

Obesity and Cancer Metastasis: Molecular and Translational Perspectives

“…TNFα enhances the CSC phenotype in numerous cell types and is associated with upregulation of stem cell related genes, chemo resistance and tumorigenesis [114][115][116]. Furthermore, TNFα upregulates TAZ (a Hippo pathway effector) and Slug (an EMT mediator), which increase breast CSCs through both canonical and non-canonical NF-κB signaling [117,118]. Analysis of TNBC patient datasets reveals high tumor expression of the epigenetic reader methyl-CpG-binding domain protein 2 (MBD2), specifically the alternative splicing variant 2 (MBD2_v2) expression and high relapse rate and high BMI [119].…”

Signaling pathways essential for triple-negative breast cancer stem-like cells

“…73 In addition, for the noncanonical NF-κB pathway it seems that TNF-α induces the expression of transcription adaptor putative zinc finger (TAZ), a transcriptional co-activator, and increases CSCs in both ER+ and TNBC cell lines. 74 TAZ do not bind to DNA directly, but can be recruited to specific target promoter sequences through binding to the TEAD transcription co-factor, and regulate the expression of genes that are essential for proliferation, apoptosis, and EMT. 75,76 NF-κB also contributes to the invasive and metastatic capabilities of CSCs, which can occur through modulation of the extracellular environment or through EMT.…”