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.

Inflammatory breast cancer (IBC) is a highly aggressive subtype of breast cancer associated with a poor prognosis. A better understanding of IBC's pathological and molecular basis is crucial for developing precision medicine strategies. This study aimed to profile IBC at both the single-cell and spatial levels to examine immune cell populations, signaling pathways, and identify potential therapeutic targets for treating IBC. Single-cell RNA sequencing (scRNA-seq) was employed to identify immune-related differences between IBC and non-IBC samples. qRT-PCR and fluorescence staining were utilized to validate the findings from scRNA-seq, while spatial analysis using the NanoString GeoMx Digital Spatial Profiler was conducted to evaluate immune cell infiltration. Tumor-immune cell co-culture assays were conducted to assess the cytotoxic role of CXCL13. In vivo studies were performed to assess the effect of CXCL13 on the efficacy of immunotherapy. Furthermore, a screening of natural products was performed to identify potential immunomodulatory agents for the treatment of IBC. scRNA-seq revealed a significant reduction in CXCL13 expression in T cells within the IBC tumor microenvironment, a finding that correlated with poorer patient outcomes. Additionally, immune-related gene sets were notably downregulated, and cell-cell interactions were diminished, indicating a state of immune suppression within IBC. Spatial analysis further demonstrated a reduced presence of CD45-positive immune cells within IBC tumor tissues, highlighting the compromised immune infiltration characteristic of this aggressive cancer subtype. Most importantly, overexpression of CXCL13 in tumor cells, under co-culture with immune cells, significantly promoted tumor cell death. CXCL13 can also enhance the efficacy of anti-PD-1 therapy in vivo. Furthermore, screening of natural products identified sanguinarine and α-mangostin as potential immunomodulatory compounds, offering promising therapeutic avenues for modulating the immune response in IBC and improving treatment outcomes. Our findings reveal inherent heterogeneity within the "cold" tumor microenvironment of IBC. These factors collectively contribute to the immune suppression characteristic of IBC. Additionally, natural product screening identified sanguinarine and α-mangostin as promising immunomodulatory agents, offering potential therapeutic strategies to improve treatment outcomes.

Breast cancer is one of the most common types of cancer among women worldwide and needs more sensitive prognostic biomarkers to improve its treatment. In the present study, differentially expressed long non‑coding RNAs (lncRNAs) in invasive breast carcinoma from The Cancer Genome Atlas and cBioPortal database were investigated, identifying 292 differentially expressed lncRNAs in 1,100 cases. By analyzing the overall survival rate, 10 lncRNAs were significantly correlated with poor prognosis. To explore the underlying molecular mechanisms of the 10 prognosis‑related lncRNAs, bioinformatic methods were used to predict the potential target miRNAs, mRNAs and proteins, and to construct a lncRNA‑miRNA‑mRNA regulatory network and lncRNA‑protein interaction network. Finally, the functions of the target genes and proteins were insvestigated using Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses. The results showed that these 10 lncRNAs could be novel prognostic markers for invasive breast carcinoma and the present study aimed to provide novel insight into the diagnosis and treatment of breast cancer.

Peripheral blood of Neutrophil-to-Lymphocyte ratio (NLR), carcinoma embryonic antigen (CEA), cancer antigen 125 (CA125) and cancer antigen 15–3 (CA15-3) could be used as prognostic indicators for several types of tumors. The purpose of this study was to evaluate the predictive value of inflammatory cell ratio and tumor markers for postoperative breast cancer patients. Clinical data concerning 190 breast cancer patients who underwent radical surgery in Zhejiang Provincial Hospital of Chinese Medicine from 2013 and 2016 were retrospectively analyzed. The effects of NLR, CEA, CA125, and CA153 on the disease-free survival (DFS) of patients with breast cancer were analyzed by χ ² test and Cox regression analyses. There were totally 32 of 190 patients had local or distant metastases within 5 years after surgery. The peripheral blood NLR, CEA, CA125, and CA15-3 areas under the curve (AUC) were 0.8272, 0.667, 0.702, and 0.715, and the optimal cutoff values were 2.65, 1.47, 10.55, and 10.55, respectively. Univariate analysis and Kaplan-Meier survival analysis revealed that the serum NLR, CEA, CA125, and CA15-3 were related to postoperative 5-year DFS (P < .05). In addition, multivariate survival analysis identified the following independent prognostic factors: NLR (P < .001), CA125 (P = .045) and ki-67 (P = .020). Preoperative serum inflammatory biomarker of NLR and tumor marker of CA125 have potential prognostic value for breast carcinoma.

Breast cancer is the most common malignant tumor among women globally, with incidence and mortality rates ranking first among female cancers. Mitochondrial dysfunction plays a crucial role in the occurrence, development, and metastasis of breast cancer, but the specific mechanisms remain unclear. This study aims to explore the mechanisms and prognostic value of the mitochondrial-related gene PARK7 in breast cancer. This study integrated summary data on the methylation levels, expression levels, and protein abundance of mitochondrial-related genes. The discovery phase data were sourced from the IEU GWAS database, while the validation phase data came from the FinnGen study dataset. Mendelian randomization and colocalization analyses were conducted to explore the potential associations between the methylation, expression, and protein abundance of mitochondrial-related genes and breast cancer risk. Clinical and pathological data, as well as gene expression data from breast cancer patients, were obtained from the TCGA database. Cox regression analysis was used to assess the relationship between PARK7 expression and clinical pathological features, and a prognostic model was constructed. Additionally, in vitro experiments were performed to verify the effects of PARK7 on triple-negative breast cancer cells. The study found that high expression of the PARK7 gene is closely related to a reduced risk of breast cancer (OR 0.91, 95% Cl 0.88–0.95; PPH4 = 0.90), which was also validated in the FinnGen dataset. Patients with high PARK7 expression had longer survival times and higher survival probabilities in the TCGA database. In vitro experiments showed that overexpression of PARK7 significantly inhibited the proliferation, migration, and colony formation of triple-negative breast cancer cells, while promoting apoptosis and significantly increasing mitochondrial membrane potential, indicating altered mitochondrial function. Furthermore, Western blot analysis revealed that overexpression of PARK7 led to increased PTEN protein expression and decreased p-PI3K and p-AKT protein expression, suggesting that PARK7 may exert its tumor-suppressive effects by modulating the PI3K/Akt signaling pathway. High expression of the PARK7 gene is closely related to reduced breast cancer risk and good prognosis, and it may exert its tumor-suppressive effects by regulating the expression of apoptosis-related proteins and migration-related proteins, as well as by affecting mitochondrial function and modulating the PI3K/Akt signaling pathway. It can serve as a potential biomarker for the diagnosis, treatment, and prognosis of breast cancer.

Background: Paclitaxel (PTX) is a cornerstone chemotherapy for Breast Cancer (BC), yet its impact is limited by emerging resistance. Elemene Injection (EI) has shown potential in overcoming chemotherapy resistance. However, the efficacy by which EI restores PTX sensitivity in BC and the implicated molecular mechanism remain uncharted. Methods: Network pharmacology and bioinformatic analysis were conducted to investigate the targets and mechanisms of EI in overcoming PTX resistance. A paclitaxel-resistant MCF-7 cell line (MCF-7PR) was established. The efficacy of EI and/or PTX in inhibiting cell viability was evaluated using sulforhodamine B assay, while cell proliferation was assessed using EdU staining. Furthermore, protein and gene expression analysis was performed through Western blotting and qPCR. Results: The EI containing three active components exhibited a multifaceted impact by targeting an extensive repertoire of 122 potential molecular targets. By intersecting with 761 differentially expressed genes, we successfully identified 9 genes that displayed a direct association with resistance to PTX in BC, presenting promising potential as therapeutic targets for the EI to effectively counteract PTX resistance. Enrichment analysis indicated a significant correlation between these identified targets and critical biological processes, particularly DNA damage response and cell cycle regulation. This correlation was further substantiated through meticulous analysis of single-cell datasets. Molecular docking analysis revealed robust binding affinities between the active components of the EI and the identified molecular targets. Subsequently, in vitro experiments unequivocally demonstrated the dose- and time-dependent inhibitory effects of the EI on both PTX-resistant and sensitive BC cell lines, effectively mitigating the resistance phenotype associated with PTX administration. Furthermore, our findings have indicated EI to effectively suppress the protein expression levels of AR and RUNX1 in MCF-7 and MCF-7PR cells under PTX treatment, as well as downregulate the mRNA expression levels of stem-like properties’ markers, KLF4 and OCT4, in these cell lines. Conclusion: Elemene Injection (EI) application has exhibited a significant capability to mitigate PTX resistance in BC, which has been achieved through targeted suppression of the AR/RUNX1 axis, revealing a key strategy to overcome chemotherapeutic resistance.