The prevalence of breast cancer among women has led to a growing need for innovative anti-breast cancer medications and an in-depth investigation into their molecular mechanisms of action, both of which are essential tactics in clinical intervention. In the clinical practice of Traditional Chinese Medicine, Radix Bupleuri and its active components have shown promise as potential anti-breast cancer agents due to their ability to target multiple pathways, exhibit synergistic effects and reduce toxicity. These compounds are considered to enhance the prognosis of patients with cancer, prolong survival and combat chemotherapy resistance. The present review aimed to delve into the anti-breast cancer properties of Radix Bupleuri and its active ingredients, highlighting their mechanisms, such as inhibition of cell proliferation, promotion of apoptosis, metastasis prevention, microenvironment improvement and synergy with certain chemotherapeutic agents. These findings may provide a scientific rationale for combining Radix Bupleuri and its active components with traditional chemotherapy agents for the management of breast cancer.

This study explores the molecular mechanism by which sentrin/SUMO-specific protease 1 (SENP1) promotes cisplatin (Cis) resistance and tumor stem cell characteristics in colon adenocarcinoma (COAD) through deSUMOylation-mediated modification of octamer-binding transcription factor 4 (OCT4). By analyzing single-cell and transcriptome sequencing datasets, we identified key genes and regulatory pathways in both resistant and sensitive COAD cells. Malignant cells were isolated and evaluated for stemness using the infercnv package, and differential genes between Cis-resistant and -sensitive groups were identified. Machine learning algorithms highlighted essential genes, and databases predicted interaction sites between OCT4 and SENP1. In vitro experiments using enriched HCT116 stem cells revealed that SENP1 and OCT4 expression significantly elevated CD44 and CD133 levels, enhancing stemness. Functional assays showed that SENP1's deSUMOylation of OCT4 intensified Cis resistance, migration, and invasion in cisplatin-resistant cell line 116 (Cis-116) cells. In vivo, SENP1 knockdown reduced tumor growth and stem cell markers, whereas OCT4 overexpression escalated tumor metastasis and structural damage. These findings demonstrate that SENP1's modulation of OCT4 is central to COAD's resistance and stem cell properties, offering a novel target for COAD therapy.NEW & NOTEWORTHY This study uncovers the critical role of SENP1 in regulating OCT4 through deSUMOylation, driving Cis resistance and tumor stemness in COAD. Targeting this pathway may provide novel therapeutic strategies for COAD management.

Cornua cervi degelatinatum (CCD) is formed by removing the gelatinous substance from deer antlers according to traditional methods. It was first recorded in the Shennong's Classic of Materia Medica and has been included in the Pharmacopoeia of the People's Republic of China. It is commonly used in clinical practice for the treatment of diseases such as cancer and infertility.

This study aims to investigate the impact of CCD aqueous extract on the proliferation and stemness of breast cancer (BC) cells, with an emphasis on its regulation of miR-148a-3p expression and associated molecular pathways.

Breast cancer cells were treated with various concentrations of CCD to assess its effects on cancer stem cell (CSC) features, epithelial-mesenchymal transition (EMT) markers, and overall plasticity. The UALCAN platform was utilized to analyze the relationship between miR-148a-3p and Smad2 expression. Functional experiments involving miR-148a-3p overexpression were performed to elucidate CCD's modulatory effects on the TGF-β/Smad2 pathway. Furthermore, molecular docking analysis was conducted to predict the binding affinity of CCD's active components to Smad2.

The CCD aqueous extract significantly reduced BC cell viability in vitro and dose-dependently suppressed the expression of stemness- and EMT-related proteins. Bioinformatics analysis and luciferase reporter assays validated miR-148a-3p as a direct regulator of Smad2, inhibiting the TGF-β/Smad2 signaling pathway. Molecular docking revealed strong binding interactions between CCD's active components and Smad2.

CCD exhibits anti-BC effects by working synergistically with miR-148a-3p to inhibit the TGF-β/Smad2 pathway, thereby reducing BC stemness and EMT progression. These findings provide valuable insights into the molecular mechanisms underlying CCD's therapeutic potential in BC treatment.

Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer, featuring a high proportion of cancer stem cells (CSCs) and the poorest clinical outcomes. Taraxacum mongolicum Hand. -Mazz., widely recognized as dandelion, is a traditional medicinal herb that has demonstrated promising anti-TNBC potential. However, the efficacy of dandelion in anti-TNBC stem-like properties remains to be elucidated.

The aim was to examine the impact of dandelion extract on the stemness properties of TNBC and to delineate the underlying mechanisms.

UHPLC-Q-Orbitrap HRMS was employed to characterize the components present in dandelion extract. Network pharmacology was utilized to explore the impact of dandelion-derived compounds on the molecular pathways associated with TNBC. The assessment of TNBC stem-like properties was conducted through mammosphere formation assays and flow cytometry analysis. Western blotting, qRT-PCR, and immunofluorescence were employed to investigate the mechanisms of dandelion extract. 4T1-luc xenograft tumor model was used to assess the anti-tumor effect of dandelion extract in vivo. IVIS imaging technology was used to monitor lung metastasis.

In this study, pharmacological network analysis revealed the potential regulatory effects of dandelion extract on TNBC stemness. Dandelion extract disrupts the stem-like properties in MDA-MB-231 and MDA-MB-468 cell lines via reducing ALDH + cells proportion, impeding mammosphere formation, and downregulating CSC-related markers, including SOX2, SOX9, NANOG, and FOXM1. Furthermore, CUE domain containing protein 2 (CUEDC2) promotes the maintenance of TNBC stemness and contributes to the anti-stemness effects of dandelion extract. Mechanistically, dandelion extract inhibits CUEDC2-mediated nuclear translocation of β-catenin, thereby reducing the transcriptional activity of OCT4. In vivo, dandelion extract suppresses tumor growth, lung metastasis, and decreases the expression of CSC-related markers.

These findings suggest that dandelion extract inhibits TNBC stem-like properties via modulating the CUEDC2/β-catenin/OCT4 signaling axis, highlighting its potential as a therapeutic option for TNBC.

Breast cancer is the most common malignant tumor in women. Among its subtypes, triple-negative breast cancer (TNBC) is more aggressive and poses a serious threat to women's health. Rosmarinic acid (RA) is a natural polyphenolic compound known for its diverse pharmacological activities, with its antioxidant and anticancer properties being particularly notable. This study investigated the effects of RA on TNBC cell lines and explored its potential mechanisms. CCK-8 and colony formation assays were used to evaluate the potential inhibitory effects of RA on TNBC cells and to measure intracellular reactive oxygen species (ROS) levels. Flow cytometry was employed to analyze the cell cycle and apoptosis. RNA-seq analysis was performed to investigate the potential mechanisms of RA on MDA-MB-231 cells. RA inhibited the proliferation of TNBC cells in a concentration-dependent manner and reduced intracellular ROS levels. RA induced cell cycle arrest at the G1/G0 phase and promoted apoptosis by decreasing mitochondrial membrane potential. RNA-seq differential expression analysis, identified 1,929 differentially expressed genes, including 601 upregulated genes and 1,328 downregulated genes. Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) showed that these differentially expressed genes were significantly enriched in pathways associated with ferroptosis, ABC transporters, and fatty acid metabolism. Additionally, RA significantly upregulated the expression of dynamin-related protein 1 (DRP1) in MDA-MB-231 cells, promoting mitochondrial fission, disrupting mitochondrial dynamics, and leading to dysfunction. Furthermore, RA increased the expression of intracellular ferroportin and heme oxygenase 1 (HMOX-1), resulting in elevated intracellular iron levels. The study suggests that RA inhibits the proliferation of TNBC cells through multiple mechanisms and may have potential therapeutic effects in the treatment of TNBC.

In the breast tumor microenvironment (TME), adipocytes exert a selective pressure on the behavior of breast cancer stem cells (BCSCs), which are involved in endocrine therapy resistance. In obesity, adipocytes secrete reduced levels of adiponectin, which promotes the growth and progression of ERα-positive breast cancer (BC). Here, we examined how low adiponectin levels affect the enrichment of the BCSC subpopulation and the mechanisms contributing to the maintenance of endocrine therapy resistance in BC. Flow cytometry, qRT-PCR, and Western blotting analysis were performed to assess stemness, the cell cycle, and apoptosis markers in MCF-7 wild-type (WT) and tamoxifen-resistant (TR) mammospheres. nLC-MS/MS was employed to profile and compare the proteome of BCSCs. Differentially expressed proteins were intersected with data from the MetacoreTM dataset. Our study demonstrated that adiponectin increased the percentage of CD44+/CD24-/ALDH1+ stem-like cells in TR MCF-7 mammospheres. Specifically, adiponectin contributed to the maintenance of BCSC bulk in TR MCF-7 cells through a slow cycling rate, supported by decreased levels of Cyclin D1 and Ki67 and increased p21 and p27 expression, and through escape from apoptosis, sustained by reduced ROS production and preserved maintenance of mitochondrial membrane potential. Our results provide new insights into the contribution of adiponectin to poor ERα-positive BC outcomes. Deeply understanding adiponectin's role in stemness may disclose novel therapeutic approaches to treat hormone-resistant obese BC patients.

Tumors frequently harbor isogenic yet epigenetically distinct subpopulations of multi-potent cells with high tumor-initiating potential-often called Cancer Stem-Like Cells (CSLCs). These can display preferential resistance to standard-of-care chemotherapy. Single-cell analyses can help elucidate Master Regulator (MR) proteins responsible for governing the transcriptional state of these cells, thus revealing complementary dependencies that may be leveraged via combination therapy. Interrogation of single-cell RNA sequencing profiles from seven metastatic breast cancer patients, using perturbational profiles of clinically relevant drugs, identified drugs predicted to invert the activity of MR proteins governing the transcriptional state of chemoresistant CSLCs, which were then validated by CROP-seq assays. The top drug, the anthelmintic albendazole, depleted this subpopulation in vivo without noticeable cytotoxicity. Moreover, sequential cycles of albendazole and paclitaxel-a commonly used chemotherapeutic -displayed significant synergy in a patient-derived xenograft (PDX) from a TNBC patient, suggesting that network-based approaches can help develop mechanism-based combinatorial therapies targeting complementary subpopulations.

Network-based approaches, as shown in a study on metastatic breast cancer, can develop effective combinatorial therapies targeting complementary subpopulations. By analyzing scRNA-seq data and using clinically relevant drugs, researchers identified and depleted chemoresistant Cancer Stem-Like Cells, enhancing the efficacy of standard chemotherapies.

Triple-negative breast cancer (TNBC) is a subtype known for its aggressive nature, high rates of recurrence, and treatment resistance, largely attributed to the presence of breast cancer stem cells (BCSCs). Traditional therapies often struggle to eliminate BCSCs, which contributes to tumor recurrence. One promising strategy for addressing this challenge is targeting the Notch signaling pathway, which plays a critical role in the self-renewal and maintenance of BCSCs. DAPT, a potent γ-secretase inhibitor that down-regulates Notch, has limited use due to poor bio-distribution and off-target effects. To achieve the targeted delivery of DAPT to TNBC cells, we encapsulated DAPT in solid lipid nanoparticles (SLNs), and the surface of SLNs was further decorated with DLL4 and DR5 antibodies to produce DLL4-DR5-DAPT@SLNs (∼256 ± 3 nm). The developed DLL4-DR5-DAPT@SLNs have been characterized using various spectroscopy and microscopy techniques. The in vitro studies demonstrated that, DLL4-DR5-DAPT@SLNs can effectively internalize, showing excellent cytotoxicity and efficiently suppress cell migration and invasion by reducing the expression of Notch-1, promote apoptosis by increasing the expression of Caspase-8 and eventually inhibit the process of EMT via up-regulating the E-cadherin and down-regulating the vimentin expression at protein level. Further, in vivo studies demonstrated that DLL4-DR5-DAPT@SLNs exhibit targeted accumulation within tumors, resulting in a notable reduction in tumor size from 2.3 cm to 0.9 cm and a decrease in tumor volume from 2506.2 ± 104.6 mm3 to 832.4 ± 93.1 mm3. The targeted treatment significantly reduced the overall tumor burden, contributing to the extension of long-term survival rates. The findings reveal that functionalization of DLL4 and DR5 significantly enhances the therapeutic delivery of DAPT to TNBC cells via simultaneously inhibiting the Notch signaling pathway and promoting apoptosis. The developed nanosystem addresses limitations associated with conventional therapies, such as insufficient targeting, systemic toxicity, and poor bioavailability. This study presents the innovative nanosystem as a potential treatment strategy for TNBC, aiming to enhance treatment efficacy and reduce off-target effects.

Tumor necrosis factor receptor-associated factor 4 (TRAF4), an E3 ubiquitin ligase, is frequently overexpressed in tumors. Although its cytoplasmic role in tumor progression is well-documented, the precise mechanisms underlying its nuclear localization and functional contributions in tumor cells remain elusive. This study demonstrated a positive correlation between the expression of nuclear TRAF4 and both tumor grades and stemness signatures in human cancer tissues. Notably, reduced nuclear TRAF4 led to decreased stemness properties and metastatic dormancy of tumor cells. Conversely, restoring nuclear TRAF4 in TRAF4-knockout (TRAF4-KO) cells augmented these cellular capabilities. Within the nucleus, the TRAF domain of TRAF4 interacted with c-Jun, thereby stimulating its transcriptional activity. This interaction subsequently led to an enhancement of the promoter activity of interleukin-8 (IL-8), which is identified as a mediator of nuclear TRAF4-induced tumor dormancy. Additionally, activation of AKT signaling by nerve growth factor facilitated TRAF4 phosphorylation at Ser242, enhancing its interaction with 14-3-3θ and promoting its nuclear translocation. Importantly, pharmacological modulation of TRAF4 nuclear translocation is found to suppress tumor tumorigenicity and metastasis in tumor models. This study highlights the critical role of nuclear TRAF4 in regulating tumor stemness and dormancy, positioning it as a potential therapeutic target for metastatic and refractory cancers.

CDK4/6 inhibitors have significantly improved the survival of patients with HR-positive/HER2-negative breast cancer, becoming a first-line treatment option. However, the development of resistance to these inhibitors is inevitable. To address this challenge, novel strategies are required to overcome resistance, necessitating a deeper understanding of its mechanisms. Recent research has identified several dysregulated genes in CDK4/6 inhibitors-resistant breast cancer, but the underlying mechanism is complex due to tumor heterogeneity and warrants further investigation.

RNA sequencing and KEGG pathway analysis was carried out to identify the mainly dysregulated genes in CDK4/6 inhibitors-resistant breast cancer cells. The effects of CXCR4 knockdown and overexpression via siRNAs and plasmids transfection were examined by mammosphere formation, RT-qPCR, flow cytometry, MTT and colony formation assays. The regulation mechanisms were analyzed by RT-qPCR, western blotting and immunofluorescence experiments. Mouse xenografts were used to analyze the role of CXCR4 in regulation palbociclib sensitivity in vivo. Additionally, we collected the clinical samples and performed immunohistochemistry to analyze the clinical significance of CXCR4.

In our study, we focused on cancer stem cells, a critical contributor to cancer metastasis and therapy resistance, and detected an upregulation of stemness in our established palbociclib-resistant ER-positive breast cancer cells. Additionally, our research pinpointed CXCR4 as a pivotal gene responsible for maintaining cancer stemness and promoting palbociclib resistance. Mechanistically, CXCR4 activates the WNT5A/β-catenin signaling pathway by enhancing the expression of WNT5A and β-catenin, facilitating the nuclear translocation of β-catenin protein. Targeting CXCR4 using siRNAs or small molecular inhibitors effectively reduces cancer stemness and reverses palbociclib resistance both in vitro and in vivo. Clinical sample analysis further underscores the overactivation of the CXCR4/WNT5A/β-catenin axis in palbociclib-resistant breast cancer, suggesting CXCR4 as a potential biomarker for predicting resistance to CDK4/6 inhibitors.

Collectively, our study demonstrates that CXCR4 overexpression plays a vital role in maintaining breast cancer stemness and promoting resistance to CDK4/6 inhibitors through the activation of the WNT5A/β-catenin pathway. Targeting CXCR4 may offer a promising therapeutic approach for advanced CDK4/6 inhibitor-resistant ER-positive breast cancer.

Cancer heterogeneity is a major challenge in oncology, complicating diagnosis, prognostication, and treatment. The clinical heterogeneity of cancer, which leads to differential treatment outcomes between patients with histopathologically similar cancers, is attributable to molecular diversity manifesting through genetic, epigenetic, transcriptomic, microenvironmental, and host biology differences. Heterogeneity is observed between patients, individual metastases, and within individual lesions. This review discusses clinical implications of heterogeneity, emphasizing need for personalized approaches to overcome challenges posed by cancer's diverse presentations. Understanding of emerging molecular diagnostic and analytical techniques can provide a view into the multidimensional complexity of cancer heterogeneity. With over 90% of cancer-related deaths associated with metastasis, we additionally explore the role heterogeneity plays in treatment resistance and recurrence of metastatic lesions. Molecular insights from next-generation sequencing, single-cell transcriptomics, liquid biopsy technology, and artificial intelligence will facilitate the development of combination therapy regimens that can potentially induce lasting and even curative treatment outcomes.

Gliomas are aggressive intracranial tumors of the central nervous system with a poor prognosis, high risk of recurrence, and low survival rates. Radiation, surgery, and chemotherapy are traditional cancer therapies. It is very challenging to accurately image and differentiate the malignancy grade of gliomas due to their heterogeneous and infiltrating nature and the obstruction of the blood-brain barrier. Imaging plays a crucial role in gliomas which significantly plays an important role in the accuracy of the diagnosis followed by any subsequent surgery or therapy. Other diagnostic methods (such as biopsies or surgery) are often very invasive. Preoperative imaging and intraoperative image-guided surgery perform the most significant safe resection. In recent years, the rapid growth of nanotechnology has opened up new avenues for glioma diagnosis and treatment. For better therapeutic efficacy, developing microenvironment-responsive nanoplatforms, including novel nanotherapeutic platforms of sonodynamic therapy, photodynamic therapy, and photothermal treatments, are employed for improved patient survival and better clinical control outcome. In this review recent advancement of multifunctional nanoplatforms leading toward treatment of glioma is discussed.

Ginsenoside Rg3 (Rg3), a bioactive compound from ginseng, is gaining attention for its potential in targeting cancer stem cells in cancer therapy. The therapeutic effect of Rg3 on breast cancer stem cells (BCSCs) has not been systematically explored using a suitable approach. Our study leverages a multi-faceted strategy, including network pharmacology, molecular docking, and in vitro experiments validation, to explore the effect of Rg3 against BCSCs. We identified 38 common targets of Rg3 and BCSCs through public databases mining. The analysis of protein-protein interaction network revealed Myc, Stat3, Bcl2, Cdh1, Egf, Il6, Egfr, Nfkb1, Sox2 and Sirt1 as the top 10 potential targets. Molecular docking further validated Rg3 has robust binding potential with these targets. Utilizing the BCSC-enriched MCF-7 and MDA-MB-231 mammosphere model, in vitro experiments substantiated Rg3's ability to induce apoptosis, suppress proliferation, and inhibit mammospheres formation of BCSCs. Rg3 also decreased the ALDHhigh and CD44+/CD24-/low subpopulations and downregulated the expression of cancer stem cell markers such as c-MYC, ALDH1A1, NANOG in BCSCs. After Rg3 treatment, most of the top 10 genes in BCSC-enriched MCF-7 mammospheres showed a significant reduction in expression, with Cdh1 (E-cadherin) being the most markedly downregulated. The E-cadherin/catenin complex acts as an upstream regulator of the Hippo signaling pathway, which is crucial for BCSC function and is among the top 20 enriched pathways identified by KEGG analysis. Mechanistically, Rg3 attenuates the stemness of BCSCs by activating the Hippo signaling pathway. This study provides a comprehensive evaluation of Rg3 as a promising therapeutic agent against BCSCs.

One of the key factors that contribute to tumor progression and resistance is the immunosuppressive microenvironment of the tumor. CD200 is a recently identified cell surface glycoprotein recognized as an important molecule in breast cancer for its versatile modulation of the immune response via its receptor, CD200R. The interaction between CD200 and CD200R suppresses the immune activities against tumor cells and allows them to be undetected and, in doing so, to escape from the destructive capability of the immune cells. Here, we review recent advances and future trends in CD200-targeted therapies for cancer treatments. We also discuss molecular pathways that include variable expressions across different cancer types and their importance in treatment options.

Breast cancer remains the leading cause of mortality among women with cancer. This article delves into the intricate relationship between breast cancer and cancer stem cells (CSCs), emphasizing advanced methods for their identification and isolation. The key isolation techniques, such as the mammosphere formation assay, surface marker identification, Side Population assay, and Aldehyde Dehydrogenase assay, are critically examined. Furthermore, the review analyzes CSC-specific molecular signaling pathways, focusing on actionable targets like CD44/CD24, Nanog, and Oct4. The potential of targeted therapies and small molecules that disrupt these pathways is explored. Additionally, the review highlights immunotherapy strategies against CSCs, focusing on resistance mechanisms and the critical role of precision medicine. The study investigates how precision medicine enhances therapeutic outcomes by targeting specific CSC biomarkers. This comprehensive analysis offers insights into recent advancements and emerging strategies in breast cancer treatment, pointing toward future therapeutic innovations.

Breast cancer stem cells (BCSCs) are the main cause of breast cancer recurrence and metastasis. While the ubiquitin-proteasome system contributes to the regulation of BCSC stemness, the underlying mechanisms remain unclear. Here, we identified ubiquitin-conjugating enzyme E2T (UBE2T) as a pivotal ubiquitin enzyme regulating BCSC stemness through systemic screening assays, including single-cell RNA sequencing (scRNA-seq) and stemness-index analysis. We found that patients with high UBE2T expression exhibited worse prognosis than those with low expression (10-year PFS: 55.95 % vs. 85.08 %), which are consistent across various subtypes of breast cancers. Genetic ablation of UBE2T suppresses BCSC stemness and tumor progression in organoids and spontaneous MMTV-PyMT mice, dependent on the transcriptional inactivation of pluripotency genes SOX2 and NANOG. Mechanically, UBE2T collaborates with the E3 ligase TRIM25 to perform K48-linked polyubiquitination and degradation of CBX6 at K214, which deficiency helps to promote the transcription of SOX2 and NANOG and enhances BCSC stemness. The pharmacological inhibitor of UBE2T significantly reduced the expression of NANOG and SOX2, suppressed tumor progression, and demonstrated synergistic effects when combined with chemotherapeutics, but not with other treatments. Collectively, our study revealed that the UBE2T-TRIM25-CBX6 axis can regulate BCSC stemness and offers a potentially therapeutic strategy to combat breast cancer in a clinical translation setting.

Gliomas, the most prevalent malignant brain tumors in the central nervous system, are marked by rapid growth, high recurrence rates, and poor prognosis. Glioblastoma (GBM) stands out as the most aggressive subtype, characterized by significant heterogeneity. The etiology of gliomas remains elusive. RNA modifications, particularly reversible methylation, play a crucial role in regulating transcription and translation throughout the RNA lifecycle. Increasing evidence highlights the prevalence of RNA methylation in primary central nervous system malignancies, underscoring its pivotal role in glioma pathogenesis. This review focuses on recent findings regarding changes in RNA methylation expression and their effects on glioma development and progression, including N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), and N7-methylguanosine (m7G). Given the extensive roles of RNA methylation in gliomas, the potential of RNA methylation-related regulators as prognostic markers and therapeutic targets was also explored, aiming to enhance clinical management and improve patient outcomes.

Breast cancer is the most prevalent malignancy among women worldwide, with breast cancer stem cells (BCSCs) being the primary drivers of metastasis and recurrence. Numerous studies have elucidated the relationship between ferroptosis and cellular stemness, identifying the Xc- system as a key regulatory mechanism governing ferroptosis. However, the interplay between CAV1 and ferroptosis, along with its implications for stemness in breast cancer, remains inadequately understood. This gap in knowledge impedes advancements in targeted therapies for breast cancer. We employed immunohistochemistry and bioinformatics analyses to demonstrate the downregulation of CAV1 in breast cancer tissues. Additionally, we utilized CCK-8 assays, EDU staining, and Transwell assays to assess cell proliferation, migration, and invasion capabilities. Furthermore, we evaluated indicators associated with ferroptosis while examining markers related to stemness through sphere culture experiments and flow cytometry techniques. Our findings indicate that CAV1 expression can induce cell death via ferroptosis while simultaneously inhibiting both cell proliferation and features of stemness by upregulating IFNGR1 and promoting ferroptosis. Moreover, our in vivo experiments revealed that overexpression of CAV1 enhances the efficacy of anti-PD-1 therapy. In conclusion, our study elucidates the regulatory role of CAV1 on ferroptosis within breast cancer contexts; it suppresses BCSC characteristics while positioning CAV1 as a promising therapeutic target for combating this disease.

Breast cancer is a major health problem, accounting for one third of all cancers in women. There is no definitive treatment for breast cancer and its incidence is increasing worldwide every year. Furthermore, breast cancer stem cells cause resistance to radiation and chemotherapy. Telomerase is an enzyme that protects telomeres and is activated in 90% of cancer cells, and telomerase activation is a hallmark of cancer. In this review, we examine telomerase activation in breast cancer and breast cancer stem cells and the therapeutic effects of telomerase inhibition in these cells. In this review, we aim to highlight the importance and impact of telomerase inhibition in the treatment of breast cancer and the lack of studies specifically in breast cancer stem cells.

Triple-negative breast cancer (TNBC) has pronounced stemness that is associated with relapse. N6-methyladenosine (m6A) plays a crucial role in shaping cellular behavior by modulating transcript expression. However, the role of m6A in TNBC stemness, as well as the mechanisms governing its abundance, has yet to be elucidated.

We analyzed proteomic and transcriptomic data derived from breast cancer cohorts, with an emphasis on m6A regulators. To unravel the role of m6A in TNBC, we employed RNA sequencing, methylated RNA immunoprecipitation sequencing, RNA immunoprecipitation, chromatin immunoprecipitation, and luciferase reporter assays with mesenchymal stem-like (MSL) TNBC models. The clinical relevance was validated using human tissue microarrays and publicly accessible databases.

Our findings indicate that the global level of m6A modification in MSL TNBC is downregulated primarily due to the loss of methyltransferase-like 14 (METTL14). The diminished m6A modification is crucial for the maintenance of TNBC stemness, as it increases the expression of yes-associated protein 1 (YAP1) by blocking YTH domain-containing family protein 2 (YTHDF2)-mediated transcript decay, thereby promoting the activation of Hippo-independent YAP1 signaling. YAP1 is essential for sustaining the stemness regulated by METTL14. Furthermore, we demonstrated that the loss of METTL14 expression results from lysine-specific demethylase 1 (LSD1)-mediated removal of histone H3 lysine 4 methylation at the promoter region, which is critical for LSD1-driven stemness in TNBC.

These findings present an epi-transcriptional mechanism that maintains Hippo-independent YAP1 signaling and plays a role in preserving the undifferentiated state of TNBC, which indicates the potential for targeting the LSD1-METTL14 axis to address TNBC stemness.

The multidomain protein BAG3 exerts pleiotropic oncogenic functions in many tumor entities including glioblastoma (GBM). Here, we compared BAG3 protein-protein interactions in either adherently cultured or stem-like cultured U251 GBM cells. In line with BAG3's putative role in regulating stem-like properties, identified interactors in sphere-cultured cells included different stem cell markers (SOX2, OLIG2, and NES), while interactomes of adherent BAG3-proficient cells indicated a shift toward involvement of BAG3 in regulation of cilium assembly (ACTR3 and ARL3). Applying a set of BAG3 deletion constructs we could demonstrate that none of the domains except the WW domain are required for suppression of cilia formation by full-length BAG3 in U251 and U343 cells. In line with the established regulation of the Hippo pathway by this domain, we could show that the WW mutant fails to rescue YAP1 nuclear translocation. BAG3 depletion reduced activation of a YAP1/AURKA signaling pathway and induction of PLK1. Collectively, our findings point to a complex interaction network of BAG3 with several pathways regulating cilia homeostasis, involving processes related to ciliogenesis and cilium degradation.

ErbB2 kinase is a key target in approximately 20% of breast cancer cases; however, ErbB2-positive cells may shift their dependence to ErbB4 upon developing resistance to ErbB2 inhibitors. Targeting ErbB4 presents a viable strategy to address this challenge. This study employs a comprehensive approach combining structure-based pharmacophore modelling, molecular docking, and MM-GBSA calculations to identify novel ErbB4 kinase inhibitors. Critical pharmacophoric features were extracted from the crystal structures of ErbB4-lapatinib, followed by virtual screening of the Chembl database to discover potential small molecule candidates. Furthermore, the ADMET profiles of 11 shortlisted candidates were assessed to verify their pharmacokinetic and toxicity properties, identifying Chembl310724, Chembl521284, and Chembl4168686 as promising inhibitors of ErbB4 kinase activity with the binding free energy (ΔGbind) values of -99.84, -89.42 and -86.06 kcal/mol, respectively. This integrated methodology not only enhances our understanding of ErbB4 inhibition but also sets a foundation for the rational design of targeted therapies addressing breast cancer with ErbB4 dependency.

Human ALDH comprise 19 subfamilies in which ALDH1A1, ALDH1A3, ALDH3A1, ALDH5A1, ALDH7A1, and ALDH18A1 are implicated in CSC. Studies have shown that ALDH can also be involved in drug resistance and standard chemotherapy regimens are ineffective in treating patients at the stage of disease recurrence. Existing chemotherapeutic drugs eliminate the bulk of tumors but are usually not effective against CSC which express ALDH+ population. Henceforth, targeting ALDH is convincing to treat the patient's post-relapse. Combination therapies that interlink signaling mechanisms seem promising to increase the overall disease-free survival rate. Therefore, targeting ALDH through ALDH inhibitors along with immunotherapies may create a novel platform for translational research. This review aims to fill in the gap between ALDH1 family members in relation to its cell signaling mechanisms, highlighting their potential as molecular targets to sensitize recurrent tumors and bring forward the future development concerning the current progress and draw backs. This review summarizes the role of cancer stem cells and their upregulation by maintaining the tumor microenvironment in which ALDH is specifically highlighted. It discusses the regulation of ALDH family proteins and the crosstalk between ALDH and CSC in relation to cancer metabolism. Furthermore, it establishes the correlation between ALDH involved signaling mechanisms and their specific targeted inhibitors, as well as their functional modularity, bioavailability, and mechanistic role in various cancers.

Breast cancer continues to be a major health concern and is currently the most commonly diagnosed cancer worldwide. Relapse, metastasis, and therapy resistance are major clinical issues that doctors need to address. We believe BYL-719, which is PI3 kinase p110а inhibitor, could also inhibit the breast cancer stem cell phenotype and epithelial-to-mesenchymal transition (EMT). In addition to the PI3K/AKT signaling pathway, BYL-719 can also inhibit essential cancer-related signaling pathways, all of which would ultimately act on the microenvironment of cancer stem cells, which is quite complicated and regulates the characteristics of tumors. These include the stemness and resistance of malignant tumors, plasticity of cancer stem cells, and anti-apoptotic features.

A three-dimensional (3D) mammosphere culture method was used in vitro to culture and collect breast cancer stem cells (BCSCs). MTT, clonogenic, and cell apoptosis assays were used to detect cell viability, self-renewal, and differentiation abilities. A sphere formation assay under 3D conditions was used to detect the mammophore inhibition rate of BYL-719. The subpopulation of CD44+CD24- was detected using flow cytometry analysis while EMT biomarkers and essential signaling pathways were detected using western blotting. All the data were analyzed using GraphPad Prism 9 software.

BCSC-like cells were obtained by using the 3D cell culture method in vitro. We confirmed that BYL-719 could inhibit BCSC-like cell proliferation in 3D cultures and that the stemness characteristics of BCSC-like cells were inhibited. The PI3K/AKT/mTOR signaling pathway could be inhibited by BYL-719, and the Notch, JAK-STAT and MAPK/ERK signaling pathways which have crosstalk in the tumor microenvironment (TME) are also inhibited. By comparing eribulin-resistant breast cancer cell lines, we confirmed that BYL-719 could effectively overcome drug resistance.

The 3D cell culture is a novel and highly effective method for enriching BCSCs in vitro. Furthermore, the stemness and EMT of BCSCs were inhibited by BYL-719 by acting on various signaling pathways. Finally, we believe that drug resistance can be overcome by targeting the BCSCs. Conjugation of BYL-719 with other anti-neoplastic agents may be a promising treatment for this in clinic.

Breast cancer, the most prevalent and aggressive tumor affecting women, requires identification of disease determinants to facilitate the development of effective therapeutic strategies. Transient receptor potential vanilloid 2 (TRPV2), an ion channel highly permeable for calcium (Ca2+), is implicated in physiological and pathological processes. Nevertheless, the role of TRPV2 in breast cancer remains poorly elucidated. In this study, we found high levels of TRPV2 expression associated with advanced malignancy, thereby suggesting its potential as a biomarker for breast cancer staging. We demonstrated that TRPV2 activation promotes breast cancer cell proliferation, migration, and invasion, while silencing of TRPV2 suppresses breast cancer progression, highlighting the oncogenic role of TRPV2. Moreover, we reveal that TRPV2 facilitates cancer progression by modulating the CaMKKβ/AMPK/ULK1-autophagic axis through mediating calcium influx, providing new insights into TRPV2 as a novel therapeutic target for breast cancer treatment.

Cancer stem cells (CSCs) have the potential to self-renew and induce cancer, which may contribute to a poor prognosis by enabling metastasis, recurrence, and therapy resistance. Hence, this study was performed to identify the association between CSC-related genes and triple-negative breast cancer (TNBC) development. Stemness gene sets were downloaded from StemChecker. Based on the online databases, a consensus clustering algorithm was conducted for unsupervised classification of TNBC samples. The variations between subtypes were assessed with regard to prognosis, tumor immune microenvironment (TIME), and chemotherapeutic sensitivity. The stemness-related gene signature was established and random survival forest analysis was employed to identify the core gene for validation experiments and tumor sphere formation assays. 499 patients with TNBC were classified into three subgroups and the Cluster 1 had a better OS than others. After that, WGCNA study was performed to identify genes important for Cluster 1 subtype. Out of all 8 modules, the subtype of Cluster 1 and the yellow module with 103 genes demonstrated the largest positive association. After that, a four-gene stemness-related signature was established. Based on the yellow module, the 39 potential pivotal genes were subjected to the random forest survival analysis to find out the gene that was relatively important for OS. KIF15 was confirmed as the targeted gene by LASSO and random survival forest analyses. In vitro experiments, the downregulation of KIF15 promoted the stemness of TNBC cells. The expression levels of stem cell markers Nanog, SOX2, and OCT4 were found to be elevated in TNBC cell lines after KIF15 inhibition. A stemness-associated risk model was constructed to forecast the clinical outcomes of TNBC patients. The downregulation of KIF15 expression in a subpopulation of TNBC stem cells may promote stemness and possibly TNBC progression.

Triple-negative breast cancer (TNBC) still one of the most challenging sub-type in breast cancer clinical. Caffeic acid (CA) derived from effective components of traditional Chinese herbal medicine has been show potential against TNBCs. Our research has found that CA can inhibit the proliferation of TNBC cells while also suppressing the size of cancer stem cell spheres. Additionally, it reduces reactive oxygen species (ROS) levels and disruption of mitochondrial membrane potential. Simultaneously, CA influences the stemness of TNBC cells by reducing the expression of the stem cell marker protein CD44. Furthermore, we have observed that CA can modulate the FOXO1/FIS signaling pathway, disrupting mitochondrial function, inducing mitochondrial autophagy, and exerting anti-tumor activity. Additionally, changes in the immune microenvironment were detected using a mass cytometer, we found that CA can induce M1 polarization of macrophages, enhancing anti-tumor immune responses to exert anti-tumor activity. In summary, CA can be considered as a lead compound for further research in targeting TNBC.

tRNA-derived small RNAs (tsRNAs) are newly discovered non-coding RNA, which are generated from tRNAs and are reported to participate in several biological processes in diseases, especially cancer; however, the mechanism of tsRNA involvement in colorectal cancer (CRC) and 5-fluorouracil (5-FU) is still unclear.

RNA sequencing was performed to identify differential expression of tsRNAs in CRC tissues. CCK8, colony formation, transwell assays, and tumor sphere assays were used to investigate the role of tsRNA-GlyGCC in 5-FU resistance in CRC. TargetScan and miRanda were used to identify the target genes of tsRNA-GlyGCC. Biotin pull-down, RNA pull-down, luciferase assay, ChIP, and western blotting were used to explore the underlying molecular mechanisms of action of tsRNA-GlyGCC. The MeRIP assay was used to investigate the N(7)-methylguanosine RNA modification of tsRNA-GlyGCC.

In this study, we uncovered the feature of tsRNAs in human CRC tissues and confirmed a specific 5' half tRNA, 5'tiRNA-Gly-GCC (tsRNA-GlyGCC), which is upregulated in CRC tissues and modulated by METTL1-mediated N(7)-methylguanosine tRNA modification. In vitro and in vivo experiments revealed the oncogenic role of tsRNA-GlyGCC in 5-FU drug resistance in CRC. Remarkably, our results showed that tsRNA-GlyGCC modulated the JAK1/STAT6 signaling pathway by targeting SPIB. Poly (β-amino esters) were synthesized to assist the delivery of 5-FU and tsRNA-GlyGCC inhibitor, which effectively inhibited tumor growth and enhanced CRC sensitive to 5-FU without obvious adverse effects in subcutaneous tumor.

Our study revealed a specific tsRNA-GlyGCC-engaged pathway in CRC progression. Targeting tsRNA-GlyGCC in combination with 5-FU may provide a promising nanotherapeutic strategy for the treatment of 5-FU-resistance CRC.

Ovarian cancer stem cells (OCSCs) significantly impact the prognosis, chemoresistance, and treatment outcomes in OC. While ferroptosis has been proven effective against OCSCs, the intricate relationship between ferroptosis and OCSCs remains incompletely understood. Here, we enriched ovarian cancer stem-like cells (OCSLCs) through mammosphere culture, as an OCSC model. OCSLCs displayed heightened ferroptosis susceptibility, correlating with elevated FXN levels compared to non-stem OC cells. FXN has recently emerged as a potential regulator in ferroptosis. FXN knockdown diminished stemness marker nanog, sphere-forming ability, increased reactive oxygen species (ROS) generation, and attenuated OCSLCs viability. FXN overexpression exacerbated ferroptosis resistance and reduced RSL3-induced cell death. FXN knockdown impeded OCSLC xenograft tumor growth and exacerbated the degeneration of peroxiredoxin 3 (PRDX3), a mitochondrial antioxidant protein participates in oxidative stress. Thus, elevated FXN in OCSLCs suppresses ROS accumulation, fostering ferroptosis resistance, and regulates the antioxidant protein PRDX3. FXN emerges as a potential therapeutic target for OC.

Non-genetic mechanisms have recently emerged as important drivers of anticancer drug resistance. Among these, the drug tolerant persister (DTP) cell phenotype is attracting more and more attention and giving a predominant non-genetic role in cancer therapy resistance. The DTP phenotype is characterized by a quiescent or slow-cell-cycle reversible state of the cancer cell subpopulation and inert specialization to stimuli, which tolerates anticancer drug exposure to some extent through the interaction of multiple underlying mechanisms and recovering growth and proliferation after drug withdrawal, ultimately leading to treatment resistance and cancer recurrence. Therefore, targeting DTP cells is anticipated to provide new treatment opportunities for cancer patients, although our current knowledge of these DTP cells in treatment resistance remains limited. In this review, we provide a comprehensive overview of the formation characteristics and underlying drug tolerant mechanisms of DTP cells, investigate the potential drugs for DTP (including preclinical drugs, novel use for old drugs, and natural products) based on different medicine models, and discuss the necessity and feasibility of anti-DTP therapy, related application forms, and future issues that will need to be addressed to advance this emerging field towards clinical applications. Nonetheless, understanding the novel functions of DTP cells may enable us to develop new more effective anticancer therapy and improve clinical outcomes for cancer patients.

Precise regulation of stem cell quiescence is essential for tissue development and homeostasis. Therefore, its aberrant regulation is intimately correlated with various human diseases. However, the detailed mechanisms of stem cell quiescence and its specific role in the pathogenesis of various diseases remain to be determined. Recent studies have revealed that the intrinsic and microenvironmental factors are the potential candidates responsible for the orderly switch between the dormant and activated states of stem cells. In addition, defects in signaling pathways related to internal and external factors of stem cells might contribute to the initiation and development of diseases by altering the dormancy of stem cells. In this review, we focus on the mechanisms underlying stem cell quiescence, especially the involvement of intrinsic and microenvironmental factors. In addition, we discuss the relationship between the anomalies of stem cell quiescence and related diseases, hopefully providing therapeutic insights for developing novel treatments.

Polyunsaturated fatty acids (PUFAs) are essential nutrients for the human body, playing crucial roles in reducing blood lipids, anti-inflammatory responses, and anticancer effect. Quinoa is a nutritionally sound food source, rich in PUFAs. This study investigates the role of quinoa polyunsaturated fatty acids (QPAs) on quelling drug resistance in colorectal cancer. The results reveal that QPA downregulates the expression of drug-resistant proteins P-gp, MRP1, and BCRP, thereby enhancing the sensitivity of colorectal cancer drug-resistant cells to the chemotherapy drug. QPA also inhibits the stemness of drug-resistant colorectal cancer cells by reducing the expression of the stemness marker CD44. Consequently, it suppresses the downstream protein SLC7A11 and leads to ferroptosis. Additionally, QPA makes the expression of ferritin lower and increases the concentration of free iron ions within cells, leading to ferroptosis. Overall, QPA has the dual-function reversing drug resistance in colorectal cancer by simultaneously inhibiting stemness and inducing ferroptosis. This study provides a new option for chemotherapy sensitizers and establishes a theoretical foundation for the development and utilization of quinoa.

Cancer is a dynamic disease, and clonal heterogeneity plays a fundamental role in tumor development, progression, and resistance to therapies. Single-cell and spatial multimodal technologies can provide a high-resolution molecular map of underlying genomic, epigenomic, and transcriptomic alterations involved in inter- and intra-tumor heterogeneity and interactions with the microenvironment. In this review, we provide a perspective on factors driving cancer heterogeneity, tumor evolution, and clonal states. We briefly describe spatial transcriptomic technologies and summarize recent literature that sheds light on the dynamical interactions between tumor states, cell-to-cell communication, and remodeling local microenvironment.

Breast cancer stem cells (BCSCs) are key players in carcinogenesis and development. Small nucleolar RNAs (snoRNAs) seem to have a crucial influence on regulating stem cell-like properties in various cancers, but the underlying mechanism in breast cancer has not been determined. In this study, we first found that the expression of SNORA51 might be strongly and positively related to BCSCs-like properties. SNORA51 expression was assessed in breast cancer tissues (n = 158 patients) by in situ hybridization. Colony formation, cell counting kit-8, and sphere formation assays were used to detect cell proliferation and self-renewal, respectively. Wound healing and transwell assays were used to detect cell migration. Coimmunoprecipitation and molecular docking were used to determine the underlying mechanism through which SNORA51 regulates BCSCs-like properties. High SNORA51 expression was associated with a worse prognosis, overall survival, and disease-free survival, in 158 breast cancer patients and was also closely related to lymph node status, ER status, the Ki-67 index, histological grade, and TNM stage. Further analysis proved that SNORA51 could enhance and maintain stem cell-like properties, including cell proliferation, self-renewal, and migration, in breast cancer. Moreover, high SNORA51 expression could reduce nucleolar RPL3 expression, induce changes in the expression of NPM1 in the nucleolus and nucleoplasm, and ultimately increase c-MYC expression. Taken together, our findings demonstrated that SNORA51 could enhance BCSCs-like properties via the RPL3/NPM1/c-MYC pathway both in vitro and in vivo. Therefore, SNORA51 might be a significant biomarker and potential therapeutic target and might even provide a new viewpoint on the regulatory mechanism of snoRNAs in breast cancer or other malignant tumors.

Breast cancer is a prevalent malignant tumor among women with an increasing incidence rate annually. Breast cancer stem cells (BCSCs) are integral in impeding tumor advancement and addressing drug resistance. Bestatin serves as an adjuvant chemotherapy, triggering apoptosis in cancer cells. In this study, the effects of bestatin on sorted BCSCs from breast cancer cell lines have been studied. Our results indicated that bestatin inhibits the migration and proliferation of breast cancer cells by reducing the stemness of BCSCs both in vitro and in vivo. Puromycin-sensitive aminopeptidase is implicated in the process through the regulation of cell cycle, resulting in heightened cell apoptosis and diminished cell proliferation of BCSCs. Our study suggest that targeting cancer stem cell may offer a promising approach in breast cancer treatment, presenting noval therapeutic strategies for patients with breast cancer.

CircRNAs are covalently closed, single-stranded RNA that form continuous loops and play a crucial role in the initiation and progression of tumors. Cancer stem cells (CSCs) are indispensable for cancer development; however, the regulation of cancer stem cell-like properties in gastric cancer (GC) and its specific mechanism remain poorly understood. We elucidate the specific role of Circ-0075305 in GC stem cell properties. Circ-0075305 associated with chemotherapy resistance was identified by sequencing GC cells. Subsequent confirmation in both GC tissues and cell lines revealed that patients with high expression of Circ-0075305 had significantly better overall survival (OS) rates than those with low expression, particularly when treated with postoperative adjuvant chemotherapy for GC. In vitro and in vivo experiments confirmed that overexpression of Circ-0075305 can effectively reduce stem cell-like properties and enhance the sensitivity of GC cells to Oxaliplatin compared with the control group. Circ-0075305 promotes RPRD1A expression by acting as a sponge for corresponding miRNAs. The addition of LF3 (a β-catenin/TCF4 interaction antagonist) confirmed that RPRD1A inhibited the formation of the TCF4-β-catenin transcription complex through competitive to β-catenin and suppressed the transcriptional activity of stem cell markers such as SOX9 via the Wnt/β-catenin signaling pathway. This leads to the downregulation of stem cell-like property-related markers in GC. This study revealed the underlying mechanisms that regulate Circ-0075305 in GCSCs and suggests that its role in reducing β-catenin signaling may serve as a potential therapeutic candidate.

The molecular chaperone heat shock protein 90 (HSP90) regulates multiple crucial signalling pathways in cancer by driving the maturation of key signalling components, thereby playing a crucial role in tumorigenesis and drug resistance in cancer. Inhibition of HSP90 results in metastable conformational collapse of its client proteins and their proteasomal degradation. Considerable efforts have been devoted to the development of small-molecule inhibitors targeting HSP90, and more than 20 inhibitors have been evaluated in clinical trials for cancer therapy. However, owing to disadvantages such as organ toxicity and drug resistance, only one HSP90 inhibitor has been approved for use in clinical settings. In recent years, HSP90 inhibitors used in combination with other anti-cancer therapies have shown remarkable potential in the treatment of cancer. HSP90 inhibitors work synergistically with various anti-cancer therapies, including chemotherapy, targeted therapy, radiation therapy and immunotherapy. HSP90 inhibitors can improve the pharmacological effects of the above-mentioned therapies and reduce treatment resistance. This review provides an overview of the use of combination therapy with HSP90 inhibitors and other anti-cancer therapies in clinical and preclinical studies reported in the past decade and summarises design strategies and prospects for these combination therapies. Altogether, this review provides a theoretical basis for further research and application of these combination therapies in the treatment of cancer.

Cancer is a comprehensive classification encompassing more than 100 forms of malignancies that manifest in diverse tissues within the human body. Recent studies have provided evidence that aberrant epigenetic modifications are pivotal indicators of cancer. Epigenetics encapsulates DNA methyltransferases as a crucial class of modifiers. DNMTs, including DNMT3A, assume central roles in DNA methylation processes that orchestrate normal biological functions, such as gene transcription, predominantly in mammals. Typically, deviations in DNMT3A function engender distortions in factors that drive tumor growth and progression, thereby exacerbating the malignant phenotype of tumors. Consequently, such abnormalities pose significant challenges in cancer therapy because they impede treatment efficacy. Non-coding RNAs (ncRNAs) represent a group of RNA molecules that cannot encode functional proteins. Recent investigation attests to the crucial significance of regulatory ncRNAs in epigenetic regulation. Notably, recent reports have illuminated the complex interplay between ncRNA expression and epigenetic regulatory machinery, including DNMT3A, particularly in cancer. Recent findings have demonstrated that miRNAs, namely miR-770-5p, miR-101, and miR-145 exhibit the capability to target DNMT3A directly, and their aberration is implicated in diverse cellular abnormalities that predispose to cancer development. This review aims to articulate the interplay between DNMT3A and the ncRNAs, focusing on its impact on the development and progression of cancer, cancer therapy resistance, cancer stem cells, and prognosis. Importantly, the emergence of such reports that suggest a connection between DNMT3A and ncRNAs in several cancers indicates that this connecting axis offers a valuable target with significant therapeutic potential that might be exploited for cancer management.