Targeting Cancer Stem Cells in Triple-Negative Breast Cancer

Park, So‐Yeon; Choi, Jang-Hyun; Nam, Jeong‐Seok

doi:10.3390/cancers11070965

Cited by 137 publications

(135 citation statements)

References 160 publications

(210 reference statements)

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“…MCF7 is ERα+ breast cancer cell line and MDA-MB-468 is triple-negative breast cancer (TNBC) cell line. It has been reported that TNBC cells are more like cancer stem cells (CSC) in terms of gene expression signature 35 .…”

Section: Tnf-α Increases Breast Cancer Stem-like Cells and Up-regulatmentioning

confidence: 99%

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

Liu

Shi

et al. 2020

Sci Rep

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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...

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Section: Tnf-α Increases Breast Cancer Stem-like Cells and Up-regulatmentioning

confidence: 99%

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

Liu

Shi

et al. 2020

Sci Rep

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“…In further connection with TNBC, stemness factors such as SOX2 and Myc are enriched in TNBC [20,21]. In fact, the gene expression signatures of TNBCs exhibited striking similarities to those of mammary stem cells [22]. The developmental Wnt/β-catenin, Notch, and Hedgehog (Hh) pathways are also more active in both CSCs and TNBC [23][24][25].…”

mentioning

confidence: 99%

“…A further shared characteristic of TNBCs and breast CSCs is epithelial-mesenchymal transition (EMT), a phenotypic change in cells and process that contributes to invasion and distant metastasis [26]. EMT-inducing transcription factors are enriched in TNBCs and mesenchymal proteins are upregulated, while epithelial proteins are down-regulated [22]. EMT confers tumor cells with CSC-like characteristics [27,28].…”

mentioning

confidence: 99%

The Missing Lnc: The Potential of Targeting Triple-Negative Breast Cancer and Cancer Stem Cells by Inhibiting Long Non-Coding RNAs

Brown

Wasson

Marcato

2020

Cells

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Treatment decisions for breast cancer are based on staging and hormone receptor expression and include chemotherapies and endocrine therapy. While effective in many cases, some breast cancers are resistant to therapy, metastasize and recur, leading to eventual death. Higher percentages of tumor-initiating cancer stem cells (CSCs) may contribute to the increased aggressiveness, chemoresistance, and worse outcomes among breast cancer. This may be particularly true in triple-negative breast cancers (TNBCs) which have higher percentages of CSCs and are associated with worse outcomes. In recent years, increasing numbers of long non-coding RNAs (lncRNAs) have been identified as playing an important role in breast cancer progression and some of these have been specifically associated within the CSC populations of breast cancers. LncRNAs are non-protein-coding transcripts greater than 200 nucleotides which can have critical functions in gene expression regulation. The preclinical evidence regarding lncRNA antagonists for the treatment of cancer is promising and therefore, presents a potential novel approach for treating breast cancer and targeting therapy-resistant CSCs within these tumors. Herein, we summarize the lncRNAs that have been identified as functionally relevant in breast CSCs. Furthermore, our review of the literature and analysis of patient datasets has revealed that many of these breast CSC-associated lncRNAs are also enriched in TNBC. Together, this suggests that these lncRNAs may be playing a particularly important role in TNBC. Thus, certain breast cancer-promoting/CSC-associated lncRNAs could be targeted in the treatment of TNBCs and the CSCs within these tumors should be susceptible to anti-lncRNA therapy.

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“…In the present study, by exploiting the mechanism of CSCs formation in GC, we identified a specific role of DDIT3 and CEBPβ, which are enriched in the tumour tissues and cells, and further mediated the CSCs stemness in GC. In fact, various studies have shown that CSCs has the ability to self‐renewal, and thereby inducing tumour proliferation, forming spheroids and promoting tumorigenesis [14] . Therefore, CSCs are believed to mediate multidrug resistance, metastasis and poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

DDIT3 modulates cancer stemness in gastric cancer by directly regulating CEBPβ

Lin

Liu

Gao

et al. 2020

Journal of Pharmacy and Pharmacology

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Objectives Cancer stem cells (CSCs) have been identified to correlate with the initiation and metastasis of tumours, and DNA damage-inducible transcript 3 (DDIT3) is associated with the poor prognosis in gastric cancer (GC). However, whether DDIT3 mediates CSCs stemness in GC is still unclear. Methods Microarray analysis and Gene Ontology (GO) were conducted to identify the differentially expressed genes in GC tissues from GC patients. The interaction between DDIT3 and CEBPb was determined using immunoprecipitation (IP) analysis. Key findings Herein, microarray analysis showed that DDIT3 expression is increased in GC tissues. qRT-PCR confirmed that DDIT3 is significantly increased in GC tissues and cancer cell lines compared with healthy tissues and normal cell lines, individually. Genetic overexpression of DDIT3 enhanced GC cell proliferation, colony-forming ability, sphere formation and CSCs stemness. Mechanistically, DDIT3 directly up-regulated the expression of transcription factor CEBPb, leading to the increased expression of CSCs markers SOX2, NANOG, OCT4 and CD133 in gastric CSCs. Genetic downregulation of CEBPb significantly abolishes DDIT3-mediated increased cell proliferation, colony-forming ability, sphere formation and CSCs stemness. Conclusion Our results demonstrated that DDIT3 promotes CSCs stemness by up-regulating CEBPb in GC that provides novel targets for the further GC therapy.

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Targeting Cancer Stem Cells in Triple-Negative Breast Cancer

Cited by 137 publications

References 160 publications

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

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

The Missing Lnc: The Potential of Targeting Triple-Negative Breast Cancer and Cancer Stem Cells by Inhibiting Long Non-Coding RNAs

DDIT3 modulates cancer stemness in gastric cancer by directly regulating CEBPβ

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