Resistant Cancer Stem Cells Research Articles

Selective Targeting of Cancer Cells by Copper Ionophores: An Overview.

Conventional cancer therapies suffer from severe off-target effects because most of them target critical facets of cells that are generally shared by all rapidly proliferating cells. The development of new therapeutic agents should aim to increase selectivity and therefore reduce side effects. In addition, these agents should overcome cancer cell resistance and target cancer stem cells. Some copper ionophores have shown promise in this direction thanks to an intrinsic selectivity in preferentially inducing cuproptosis of cancer cells compared to normal cells. Here, Cu ionophores are discussed with a focus on selectivity towards cancer cells and on the mechanisms responsible for this selectivity. The proposed strategies, to further improve the targeting of cancer cells by copper ionophores, are also reported.

Dissecting Tumor Growth: The Role of Cancer Stem Cells in Drug Resistance and Recurrence.

Simple SummaryCancer is one of the most debated problems all over the world. Cancer stem cells are considered responsible of tumor initiation, metastasis, drug resistance, and recurrence. This subpopulation of cells has been found into the tumor bulk and showed the capacity to self-renew, differentiate, up to generate a new tumor. In the last decades, several studies have been set on the molecular mechanisms behind their specific characteristics as the Wnt/β-catenin signaling, Notch signaling, Hedgehog signaling, transcription factors, etc. The most powerful part of CSCs is represented by the niches as “promoter” of their self-renewal and “protector” from the common oncological treatment as chemotherapy and radiotherapy. In our review article we highlighted the primary mechanisms involved in CSC tumorigenesis for the setting of further targets to control the metastatic process.Emerging evidence suggests that a small subpopulation of cancer stem cells (CSCs) is responsible for initiation, progression, and metastasis cascade in tumors. CSCs share characteristics with normal stem cells, i.e., self-renewal and differentiation potential, suggesting that they can drive cancer progression. Consequently, targeting CSCs to prevent tumor growth or regrowth might offer a chance to lead the fight against cancer. CSCs create their niche, a specific area within tissue with a unique microenvironment that sustains their vital functions. Interactions between CSCs and their niches play a critical role in regulating CSCs’ self-renewal and tumorigenesis. Differences observed in the frequency of CSCs, due to the phenotypic plasticity of many cancer cells, remain a challenge in cancer therapeutics, since CSCs can modulate their transcriptional activities into a more stem-like state to protect themselves from destruction. This plasticity represents an essential step for future therapeutic approaches. Regarding self-renewal, CSCs are modulated by the same molecular pathways found in normal stem cells, such as Wnt/β-catenin signaling, Notch signaling, and Hedgehog signaling. Another key characteristic of CSCs is their resistance to standard chemotherapy and radiotherapy treatments, due to their capacity to rest in a quiescent state. This review will analyze the primary mechanisms involved in CSC tumorigenesis, with particular attention to the roles of CSCs in tumor progression in benign and malignant diseases; and will examine future perspectives on the identification of new markers to better control tumorigenesis, as well as dissecting the metastasis process.

The IVF-generated human embryonic microenvironment reverses progestin resistance in endometrial cancer cells by inducing cancer stem cell differentiation.

Progestin resistance is a critical factor that prevents patients with endometrial cancer (EC) from receiving conservative therapy. However, the etiology remains elusive. Cancer stem cells (CSCs) may be a contributing factor to progestin resistance in EC. These cells share similar stemness properties with embryonic stem cells that have a multipotent but differential naïve phenotype. Embryonic stem cells are programed to self-renew, to differentiate and to show plasticity toward a normal cellular phenotype in their defined microenvironment. However, whether this microenvironment may promote CSC differentiation toward a better responsive phenotype and reverse progestin resistance has not yet been clarified. In the current study, we found that progestin resistance of endometrial CSCs can be improved or reversed by using in vitro fertilization (IVF)-generated embryonic sac-derived fluid containing the embryonic microenvironment. Furthermore, suppression or reversal of progestin resistance was mediated by placental alkaline phosphatase (ALPP), a factor secreted into the embryonic microenvironment by IVF-generated blastocysts. ALPP significantly reversed progestin resistance by facilitating endometrial CSC differentiation through downregulating the stemness genes NANOG, OCT4 and SOX2. We further showed that the downregulation of NANOG, OCT4 and SOX2 by ALPP was carried out by TET1/2-mediated epigenetic modulation of the promoter regions of these genes. Such changes at the molecular level initiated endometrial CSC differentiation and promoted a better responsive endometrial cancer phenotype. In fact, their response to progestin treatment was similar to that of well-differentiated endometrioid carcinoma cells without CSCs. ALPP could be a novel target in the process to overcome progestin resistance, and such findings may provide a new approach for the conservative treatment of endometrial cancer.

Anti-Proliferative and Pro-Apoptotic Effects Of Dipsacus Asperoides in a Cellular Model for Triple-Negative Breast Cancer

Background: Triple negative breast cancer (TNBC) lacks expressions of estrogen receptor-α (ER-α), progesterone receptor (PR) and amplified human epidermal growth factor receptor-2 (HER-2). Current treatment for TNBC includes anthracyclin, taxol and cisplatin-based conventional chemotherapy and survival pathway PARP, PI3K, AKT and mTOR selective targeted therapy. These treatments exhibit dose-limiting systemic toxicity and presence of drug resistant cancer stem cells, which highlight the need for identification of efficacious testable alternatives that are not toxic to non-tumorigenic cells. Dipsacus asperoides (DA) is a Chinese nutritional herb and its root represents a common ingredient in Chinese herbal formulations used in women for estrogen related health issues, osteoporosis and breast diseases. This study aims to investigate the growth inhibitory effects of DA, and to detect mechanisms for its efficacy. Methods: Human mammary carcinoma derived triple negative MDA-MB-231 cell line represented the TNBC model. Non-fractionated aqueous extract from DA represented the test agent. Anchorage dependent growth, anchorage independent (AI) colony formation and cell cycle progression quantified growth inhibition. Western blot-based analysis for inhibition of RAS, PI3K and AKT and RB signaling identified mechanistic leads. Results: Treatment with DA induced a dose dependent cytostatic growth arrest (IC50:15 µg/ml; IC90: 30 µg/ml), reduced AI growth and inhibited cell cycle progression via G2/M arrest. DA affected the RAS, PI3K, AKT and RB signaling pathways, and functioned as a natural inhibitor of cyclin dependent kinase 4/6. Cellular apoptosis paralleled increase in pro-apoptotic Caspase 3/7 activity. Conclusion: These results demonstrate that DA inhibited growth, affected cell cycle progression, induced apoptosis and inhibited cancer cell survival pathways. This study validates a mechanism-based approach to identifying testable substitutes for secondary prevention/therapy of TNBC.

Unexplored Functions of Sex Hormones in Glioblastoma Cancer Stem Cells.

Biological sex impacts a wide array of molecular and cellular functions that impact organismal development and can influence disease trajectory in a variety of pathophysiological states. In nonreproductive cancers, epidemiological sex differences have been observed in a series of tumors, and recent work has identified previously unappreciated sex differences in molecular genetics and immune response. However, the extent of these sex differences in terms of drivers of tumor growth and therapeutic response is less clear. In glioblastoma (GBM), the most common primary malignant brain tumor, there is a male bias in incidence and outcome, and key genetic and epigenetic differences, as well as differences in immune response driven by immune-suppressive myeloid populations, have recently been revealed. GBM is a prototypic tumor in which cellular heterogeneity is driven by populations of therapeutically resistant cancer stem cells (CSCs) that underlie tumor growth and recurrence. There is emerging evidence that GBM CSCs may show a sex difference, with male tumor cells showing enhanced self-renewal, but how sex differences impact CSC function is not clear. In this mini-review, we focus on how sex hormones may impact CSCs in GBM and implications for other cancers with a pronounced CSC population. We also explore opportunities to leverage new models to better understand the contribution of sex hormones vs sex chromosomes to CSC function. With the rising interest in sex differences in cancer, there is an immediate need to understand the extent to which sex differences impact tumor growth, including effects on CSC function.

Significant co-expression of putative cancer stem cell markers, EpCAM and CD166, correlates with tumor stage and invasive behavior in colorectal cancer

BackgroundThe crucial oncogenic role of cancer stem cells (CSCs) in tumor maintenance, progression, drug resistance, and relapse has been clarified in different cancers, particularly in colorectal cancer (CRC). The current study was conducted to evaluate the co-expression pattern and clinical significance of epithelial cell adhesion molecules (EpCAM) and activated leukocyte cell adhesion (CD166 or ALCAM) in CRC patients.MethodsThis study was carried out on 458 paraffin-embedded CRC specimens by immunohistochemistry on tissue microarray (TMA) slides.ResultsElevated expression of EpCAM and CD166 was observed in 61.5% (246/427) and 40.5% (164/405) of CRC cases. Our analysis showed a significant positive association of EpCAM expression with tumor size (P = 0.02), tumor stage (P = 0.007), tumor differentiate (P = 0.005), vascular (P = 0.01), neural (P = 0.01), and lymph node (P = 0.001) invasion. There were no significant differences between CD166 expression and clinicopathological parameters. Moreover, the combined analysis demonstrated a reciprocal significant correlation between EpCAM and CD166 expression (P = 0.02). Interestingly, there was a significant positive correlation between EpCAM/CD166 phenotypes expression and tumor stage (P = 0.03), tumor differentiation (P = 0.05), neural, and lymph node invasion (P =0.01).ConclusionsThe significant correlation of EpCAM and CD166 expression and their association with tumor progression and aggressive behavior is the reason for the suggestion of these two CSC markers as promising targets to promote novel effective targeted-therapy strategies for cancer treatment in the present study.

Stimulation of Let-7 Maturation by Metformin Improved the Response to Tyrosine Kinase Inhibitor Therapy in an m6A Dependent Manner.

The molecular mechanism of the tyrosine kinase inhibitor (TKI) resistant lung adenocarcinoma is currently unclear, and the role of methylated adenosine at the N6 position in the resistance of cancer stem cells (CSCs) therapy is unknown. This study identified a novel and effective strategy to enhance TKIs therapy response. We first confirmed the sensitization of Metformin enforcing on Osimertinib treatment and revealed the mature miRNAs signatures of the Osimertinib resistant H1975 and HCC827 cells. Let-7b expression was stimulated when adding Metformin and then increasing the therapy sensitivity by decreasing the stem cell groups expanding. Methyltransferase-like 3 (METTL3) increased the pri-Let-7b, decreased both the pre-Let-7b and mature Let-7b, attenuating the Let-7b controlling of stem cell renewal. The addition of Metformin increased the bindings of DNA methyltransferase-3a/b (DNMT3a/b) to the METTL3 promoter. With the help of the readers of NKAP and HNRNPA2B1, the cluster mediated m6A formation on pri-Let-7b processing increased the mature Let-7b, the key player in suppressing Notch signaling and re-captivating Osimertinib treatment. We revealed that the maturation processing signaling stimulated the methylation regulation of the miRNAs, and may determine the stemness control of the therapy resistance. Our findings may open up future drug development, targeting this pathway for lung cancer patients.

Development of novel strategies to overcome therapeutic resistance of cancer stem cells

Development of novel strategies to overcome therapeutic resistance of cancer stem cells

Cancer Stem Cells Contribute to Drug Resistance in Multiple Different Ways.

Many tumors are resistant to conventional cancer therapies because a tumor is composed of heterogeneous cell population. Especially, subpopulation of cancer stem cells, which have self-renewal and differentiation properties and responsible for the tumor initiation, is generally considered resistant to chemo-, radio-, and immune therapy. Understanding the mechanism of drug resistance in cancer stem cells should lead to establish more effective therapeutic strategies. Actually, different molecular mechanisms are conceivable for cancer stem cells acquiring drug resistance. These mechanisms include not only cytoplasmic signaling pathways but also the intercellular communications in the tumor microenvironment. Recently, a great deal of successful reports challenged to elucidate the mechanisms of drug resistance and to develop novel treatments targeting cancer stem cells.

Drug and apoptosis resistance in cancer stem cells: a puzzle with many pieces.

Resistance to anticancer agents and apoptosis results in cancer relapse and is associated with cancer mortality. Substantial data have provided convincing evidence establishing that human cancers emerge from cancer stem cells (CSCs), which display self-renewal and are resistant to anticancer drugs, radiation, and apoptosis, and express enhanced epithelial to mesenchymal progression. CSCs represent a heterogeneous tumor cell population and lack specific cellular targets, which makes it a great challenge to target and eradicate them. Similarly, their close relationship with the tumor microenvironment creates greater complexity in developing novel treatment strategies targeting CSCs. Several mechanisms participate in the drug and apoptosis resistance phenotype in CSCs in various cancers. These include enhanced expression of ATP-binding cassette membrane transporters, activation of various cytoprotective and survival signaling pathways, dysregulation of stemness signaling pathways, aberrant DNA repair mechanisms, increased quiescence, autophagy, increased immune evasion, deficiency of mitochondrial-mediated apoptosis, upregulation of anti-apoptotic proteins including c-FLIP [cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein], Bcl-2 family members, inhibitors of apoptosis proteins, and PI3K/AKT signaling. Studying such mechanisms not only provides mechanistic insights into these cells that are unresponsive to drugs, but may lead to the development of targeted and effective therapeutics to eradicate CSCs. Several studies have identified promising strategies to target CSCs. These emerging strategies may help target CSC-associated drug resistance and metastasis in clinical settings. This article will review the CSCs drug and apoptosis resistance mechanisms and how to target CSCs.

The relationship between autophagy and multidrug resistance in cancer stem cells

Cancer stem cells (CSCs) are considered the origin of tumors and cancer. Recently, CSCs have been described as the cause of multidrug resistance (MDR) in almost all cancers. The MDR phenotype of CSCs manifests as the upregulation of ATP-binding cassette subfamily G, isoform 2 protein (ABCG2) in the cell membranes of CSCs. However, recent studies have demonstrated a relationship between MDR and the autophagy process of CSCs. Based on publications indexed in PubMed, Google Scholar, and Scopus, this review summarizes the relationship between autophagy and MDR in CSCs and the approaches to targeting autophagy to reduce MDR in CSCs. Autophagy can be considered a new target to overcome MDR in cancer treatment.

Identification of Biomarkers Associated with Hepatocellular Carcinoma Stem Cell Characteristics Based on Co-Expression Network Analysis of Transcriptome Data and Stemness Index.

Mounting evidence has revealed the key role of cancer stem cells in hepatocellular carcinoma (HCC) metastasis and therapy resistance, yet the genes maintaining HCC stem cell features remain to be explored. This study aimed to identify and validate the key biomarkers associated with HCC stemness. mRNA expression-based stemness index (mRNAsi) was calculating using one-class logistic regression algorithm. RNA-sequencing data and clinical information of HCC samples were downloaded from the cancer genome atlas (TCGA) and merged with the corresponding mRNAsi. We investigated the correlation between mRNAsi and HCC clinical characteristics, including tumor grades, pathologic stages, vascular invasion, and survival outcomes. Significant genes associated HCC stemness features were screened through weighted gene co-expression network analysis (WGCNA) and were functionally annotated using enrichment analysis. Protein-protein interaction network was constructed among significant genes and the key biomarkers were finally identified based on the maximal clique centrality (MCC) method. The expression of key biomarkers and its correlation with HCC clinical outcomes were validated using oncomine and gene expression omnibus (GEO) database. mR-NAsi was significantly higher in HCC tissues and gradually increased according to tumor grades and pathologic stages. Patients with vascular invasion or poor survival exhibited higher mRNAsi. Forty-four highly-correlated significant gens were screened through WGCNA and functionally related to cell cycle, cellular senescence, p53 signaling pathway, DNA replication, and mismatch repair. Four different GEO datasets confirmed that the expression levels of these 44 genes were notably higher in HCC tissues. We finally identified 15 key biomarkers (KIF4A, TTK, CCNB1, CDC20, NCAPG, CCNB2, CDC45, UBE2C, CENPA, AURKB, RRM2, CDCA8, BIRC5, TPX2, and KIF2C) through MCC method. The expression of these biomarkers was up-regulated in multiple types of cancers and showed a gradually increasing trend with HCC tumor grades. Furthermore, high expression levels of these biomarkers were also correlated with HCC metastasis, recurrence, sorafenib resistance, and poor overall survival. We identified 15 key biomarkers associated with HCC stemness features and these genes might serve as promising therapeutic targets for HCC.

Combination effect of doxorubicin and HIF inhibitor on MCF-7 CD44+/CD24- subpopulation cells in hypoxic condition

Hypoxia-inducible factors (HIFs) and cancer stem cells (CSCs) are two challenging causes of radiotherapy and chemotherapy resistance, leading to most cases of failure and recurrence in breast cancer therapy. This study was conducted to investigated the inhibitory effect of combination therapy with doxorubicin (an anthracycline) and FM19G11 (an HIF inhibitor) on MCF-7 cells and their CSC-like cells (CSC-LCs). MCF-7 CSC-LCs with a CD44+/CD24- phenotype were sorted and characterized by flow cytometry. A combination of doxorubicin and FM19G11 caused more cytotoxic effects on MCF-7 and CSC-LCs compared to doxorubicin monotherapy. The largest synergistic effect was observed in CSC-LCs under hypoxic conditions; however, MCF-7 cells showed no synergism in normoxic conditions. The administration of doxorubicin and FM19G11 induced late apoptotic and necrotic cell death in MCF-7 and CSC-LCs. Additionally, G2 phase arrest was observed in both cells. Our results demonstrated that co-administration of FM19G11 and doxorubicin had a synergistic effect in hypoxia and improved drug resistance in breast cancer stem cells.

Epithelial-Mesenchymal Transition and Cancer Stem Cells.

Epithelial-mesenchymal transition (EMT), a cellular phenotypic change from epithelial to mesenchymal-like features, is related to the resistance and metastasis of cancer stem cells (CSCs). Several signal transduction mechanisms induce EMT, which causes the gene expression alteration to induce the acquisition of resistance and metastasis in cancer. EMT is characterized with high gene expression of cadherin 2 (N-cadherin) and vimentin, and sparse cell-cell junction. The cells with EMT-phenotype have migration, metastasis and drug-resistance capacity, which are main characteristics of CSCs. It seems that the main population of CSCs exhibits EMT phenotype, whereas some populations consist of phenotypes other than EMT. In this chapter, EMT mechanism, phenotypic features of EMT and CSCs, signal transduction in EMT and CSCs, differences between EMT and CSCs, and the role of EMT in CSCs are described.

A bioinspired redox-modulating copper(II)-macrocyclic complex bearing non-steroidal anti-inflammatory drugs with anti-cancer stem cell activity.

Copper(II) coordination compounds have been investigated for their anticancer properties for decades, however, none have reached advanced human clinical trials. The poor translation of copper(II) complexes from in vitro studies to (pre)clinical studies can be attributed to their limited efficacy in animal models, which is largely associated with copper leaching and speciation (in biological fluids). Here we report a biologically stable copper(II) complex based on the active site of Type I Cu electron transport proteins. The copper(II) complex 1 comprises of dithiacyclam (with soft and hard donor atoms) and two diclofenac units, a nonsteriodial anti-inflammatory drug (NSAID). Extensive biophysical and electrochemical studies show that the solid state structure of 1 is preserved in solution and that it can access both copper(I) and copper(II) oxidation states without leaching copper or undergoing speciation (in the presence of a cellular reductant). Cell studies show that 1 kills bulk breast cancer cells and highly resistant breast cancer stem cells (CSCs) at micromolar concentrations, and is significantly less toxic towards a panel of non-cancerous cells. Clinically relevant spheroid studies show that 1 is able to inhibit breast CSC-enriched mammosphere formation to a similar extent as salinomycin, a gold standard anti-CSC agent. Mechanistic studies show that 1 evokes breast CSC death by elevating intracellular reactive oxygen species (ROS) and inhibiting cyclooxygenase-2 (COX-2) activity. The former leads to the activation of stress pathways (JNK and p38), which culminates in caspase-dependent apoptosis. This study reinforces the therapeutic potential of copper(II)-NSAID complexes and provides a bioinspired route to develop stable, ROS-generating copper-based anti-CSC drug candidates.

Role of Tumor Microenvironment in Cancer Stem Cells Resistance to Radiotherapy.

Cancer is a chronic disorder that involves several elements of both the tumor and the host stromal cells. At present, the complex relationship between the various factors presents in the tumor microenvironment (TME) and tumor cells, as well as immune cells located within the TME, is still poorly known. Within the TME, the crosstalk of these factors and immune cells essentially determines how a tumor reacts to the treatment and how the tumor can ultimately be destroyed, remain dormant, or develop and metastasize. Also, in TME, reciprocal crosstalk between cancer-associated fibroblasts (CAFs), extracellular matrix (ECM), hypoxia-inducible factor (HIF) intensifies the proliferation capacity of cancer stem cells (CSCs). CSCs are a subpopulation of cells that reside within the tumor bulk and have the capacity to self-renew, differentiate, and repair DNA damage. These characteristics make CSCs develop resistance to a variety of treatments, such as radiotherapy (RT). RT is a frequent and often curative treatment for local cancer which mediates tumor elimination by cytotoxic actions. Also, cytokines and growth factors that are released into TME have been involved in the activation of tumor radioresistance and the induction of different immune cells, altering local immune responses. In this review, we discuss the pivotal role of TME in the resistance of CSCs to RT.

Cancer stem cell-mediated therapeutic resistance in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy. In the clinic, therapeutic resistance is largely attributed to tumor heterogeneity. Growing evidence indicates that cancer stem cells (CSCs) are the major source of tumor heterogeneity. Hence, uncovering the resistance mechanisms associated with CSC properties is essential for developing effective therapeutics. CSCs resemble embryonic stem cells. Embryonic development-related genes and signaling pathways are usually abnormally active and function as oncofetal drivers in HCC. Multiple strategies have been applied to identify oncofetal drivers. The mechanisms of CSC resistance could also provide reliable biomarkers to predict treatment failure. Precisely targeting these specific CSC properties may be effective in preventing or annihilating therapy resistance. This review provides an overview of drug resistance mechanisms associated with CSC traits and summarize therapeutic strategies against drug resistance.

Role of Tumor Microenvironment in Cancer Stem Cells Resistance to Radiotherapy

Role of Tumor Microenvironment in Cancer Stem Cells Resistance to Radiotherapy

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) sensitize melanoma cells to MEK inhibition and inhibit metastasis and relapse by inducing degradation of AXL.

Melanoma is highly heterogeneous with diverse genomic alterations and partial therapeutic responses. The emergence of drug-resistant tumor cell clones accompanied by a high AXL expression level is one of the major challenges for anti-tumor clinical care. Recent studies have demonstrated that high AXL expression in melanoma cells mediated drug resistance, epithelial-mesenchymal transition (EMT), and elevated survival of cancer stem cells (CSCs). Given that we have identified several non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin potently induce the degradation of AXL, we questioned whether NSAIDs could counteract the AXL-mediated neoplastic phenotypes. In this study, we found that NSAIDs downregulate PKA activity via the PGE2 /EP2/cAMP/PKA signaling pathway and interrupt the PKA-dependent interaction between CDC37 and HSP90, resulting in an incorrect AXL protein folding and finally AXL degradation through the ubiquitination-proteasome system (UPS) pathway. Furthermore, NSAIDs not only sensitized the MEK inhibitor treatment but also reduced EMT and relapse mediated by AXL in tumor tissue. Our findings suggest that the combination of inhibitors and NSAIDs, especially aspirin, could be a simple but efficient modality to treat melanoma in which AXL is a key factor for drug resistance, metastasis, and relapse.

YB1 Is a Major Contributor to Health Disparities in Triple Negative Breast Cancer.

Simple SummaryTriple negative breast cancer (TNBC) is a devastating disease that affects many women, due to the lack of FDA-approved targeted therapy. In the absence of cell surface receptors ER, PR, and Her2 that can be targeted with hormonal and antibody treatments, cytotoxic chemotherapy remains the major course of treatment, with a dismal response and rapid recurrence due to the acquisition of resistance. TNBC is also twice as more prevalent in African American (AA) when compared to Caucasian American (CA) women. This study investigated the role of the YB1 gene in the disparities in TNBC between AA and CA women. We found that YB1 is highly expressed in TNBC tumors of AA origin when compared to CAs. Increased expression levels and activity of YB1 correlates with poor disease outcomes, resistance to chemotherapy, and the activation of the cancer stem cell (CSC) phenotype, with higher levels in AA than in CA TNBC tumors. More importantly, we found that the targeted inhibition of the expression and activity of YB1 significantly inhibited the oncogenic behavior of AA tumors through sensitization to chemotherapy and inhibition of CSCs. Our study is the first to show that YB1 activity may be a major biological contributor to the health disparities in TNBC, and that development of therapies that specifically target YB1 could reduce these disparities.Triple negative breast cancer (TNBC) is the most aggressive amongst all breast cancer (BC) subtypes. While TNBC tumors represent less than 20% of all BC subtypes, they are responsible for the most BC-related deaths. More significantly, when considering TNBC incidence across all racial/ethnic groups, TNBC accounts for less than 20% of all BCs. However, in non-Hispanic black women, the incidence rate of TNBC is more than 40%, which may be a contributing factor to the higher BC-related death rate in this population. These disparities remain strong even after accounting for differences in socioeconomic status, healthcare access, and lifestyle factors. Increased evidence now points to biological mechanisms that are intrinsic to the tumor that contribute to disparate TNBC disease burdens. Here, we show that YB1, a multifunction gene, plays a major role in the TNBC disparities between African American (AA) and Caucasian American (CA) women. We show in three independent TNBC tumors cohorts, that YB1 is significantly highly expressed in AA TNBC tumors when compared to CAs, and that increased levels of YB1 correlate with poor survival of AA patients with TNBC. We used a combination of genetic manipulation of YB1 and chemotherapy treatment, both in vitro and in animal models of TNBC to show that YB1 oncogenic activity is more enhanced in TNBC cell lines of AA origin, by increasing their tumorigenic and aggressive behaviors, trough the activation of cancer stem cell phenotype and resistance to chemotherapeutic treatments.