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Esophageal cancer (EC) is one of the most common highly malignant tumors of the digestive system, with a poor prognosis under current treatment regimens. Nucleolin (NCL) is overexpressed in many tumors, and drugs specifically targeting NCL may offer a promising strategy for treating esophageal cancer. Here, we designed and prepared a novel aptamer-conjugated drug targeting NCL by AS1411 aptamer-human serum albumin (HSA)-the apoprotein of lidamycin (LDP)-active enediyne chromophore (AE), in order to achieve targeted treatment of esophageal cancer. The experimental results revealed that AS1411-HSA-LDP effectively binds to esophageal cancer cells and could be efficiently internalized by esophageal cancer cells. In the KYSE520 xenograft tumor nude mouse model, AS1411-HSA-LDP could be targeted and enriched in the tumor location for a long time. AS1411-HSA-LDP-AE exhibited a strong cell-killing activity in esophageal cancer cells, inhibited cell migration and invasion, and induced cell apoptosis. The animal studies confirmed that AS1411-HSA-LDP-AE exhibited a strong anti-tumor effect. These findings suggested that the novel NCL-targeting aptamer-drug conjugate constructed based on lidamycin exhibited a strong anti-tumor effect, providing a promising strategy for the targeted treatment of esophageal cancer. [ABSTRACT FROM AUTHOR]

Background: It is worthwhile to establish a prognostic prediction model based on microenvironment cells (MCs) infiltration and explore new treatment strategies for triple-negative breast cancer (TNBC). Methods: The xCell algorithm was used to quantify the cellular components of the TNBC microenvironment based on bulk RNA sequencing (bulk RNA-seq) data. The MCs index (MCI) was constructed using the least absolute shrinkage and selection operator Cox (LASSO-Cox) regression analysis. Single-cell RNA sequencing (scRNA-seq), spatially resolved transcriptomics (SRT), and multiplex immunofluorescence (mIF) staining analyses verified MCI. The mechanism of action of the MCI was investigated in tumor-bearing mice. Results: MCI consists of the six types of MCs, which can precisely predict the prognosis of the TNBC patients. scRNA-seq, SRT, and mIF analyses verified the existence and proportions of these cells. Furthermore, combined with the spatial distribution characteristics of the six types of MCs, an MCI-enhanced (MCI-e) model was constructed, which could predict the prognosis of the TNBC patients more accurately. More importantly, inhibition of the insulin signaling pathway activated in the cancer cells of the MCIhigh the TNBC patients significantly prolonged the survival time of tumor-bearing mice. Conclusions: Overall, our results demonstrate that MCs infiltration can be exploited as a novel indicator for the prognosis and therapeutic regimen selection of the TNBC patients. [ABSTRACT FROM AUTHOR]

Background: Up to 23% of breast cancer patients recurred within a decade after trastuzumab treatment. Conversely, one trial found that patients with low HER2 expression and metastatic breast cancer had a positive response to trastuzumab-deruxtecan (T-Dxd). This indicates that relying solely on HER2 as a single diagnostic marker to predict the efficacy of anti-HER2 drugs is insufficient. This study highlights the interaction between histamine N-methyltransferase (HNMT) and HER2 as an adjunct predictor for trastuzumab response. Furthermore, modulation of HER2 expression by HNMT may explain why those with low HER2 expression still respond to T-Dxd. Methods: We investigated the impact of HNMT protein expression on the efficacy of anti-HER2 therapy in both in vivo and ex vivo models of patient-derived xenografts and cell line-derived xenografts. Our analysis included Förster resonance energy transfer (FRET) to assess the interaction strength between HNMT and HER2 proteins in trastuzumab-resistant and sensitive tumor tissues. Additionally, we used fluorescence lifetime imaging microscopy (FLIM), cleaved luciferase, and immunoprecipitation to study the interaction dynamics of HNMT and HER2. Furthermore, we evaluated the influence of HNMT activity on the binding of anti-HER2 antibodies to their targets through flow cytometry. We also observed the nuclear translocation of HNMT/HER2-ICD cells using fluorescent double staining and DeltaVision microscopy. Finally, ChIP sequencing was employed to identify target genes affected by the HNMT/HER2-ICD complex. Results: This study highlights HNMT as a potential auxiliary biomarker for diagnosing HER2 + breast cancer. FRET analysis demonstrated a significant interaction between HNMT and HER2 protein in trastuzumab-sensitive tumor tissue (n = 50), suggesting the potential of HNMT as a predictor of treatment response. Mechanistic studies revealed that the interaction between HNMT and HER2 contributes to increased HER2 protein expression at the transcriptional level, thereby impacting the efficacy of anti-HER2 therapy. Furthermore, a subset of triple-negative breast cancers characterized by HNMT overexpression was found to be sensitive to HER2 antibody–drug conjugates such as T-Dxd. Conclusions: These findings offer crucial insights for clinicians evaluating candidates for anti-HER2 therapy, especially for HER2-low breast cancer patients who could gain from T-Dxd treatment. Identifying HNMT expression could help clinicians pinpoint patients who would benefit from anti-HER2 therapy. [ABSTRACT FROM AUTHOR]

Background: Pharmacological vitamin C (Vit-C), or high-dose Vit-C has recently gained attention as a potential cancer therapeutic. However, the anticancer activity of Vit-C has not been investigated in realistic 3D models of human cancers, especially with respect to breast cancer (BC), and its potential benefits remain under debate. Herein, we investigate the activity and mechanism of action of pharmacological Vit-C on two BC tumor spheroids. Methods: We developed two distinct types of BC tumor spheroids from MDA-MB-231 and MCF-7 cells. The spheroids underwent treatment with a range of concentrations of pharmacological Vit-C (1, 5, 10, 15, and 20 mM). Assessments were conducted to determine the cell viability, H2O2 levels, glutathione-to-glutathione disulfide (GSH/GSSG) ratios, and apoptosis. Both flow cytometry analyses of Annexin V/PI staining and caspase3/7 activity assay were used to check apoptosis. Results: We showed that Vit-C induced dose-dependent cell death in both types of tumor spheroids, primarily driven by elevated H2O2 production and a concomitant oxidative stress imbalance induced by the GSH depletion. The high levels of H2O2 generated by Vit-C triggered the apoptosis of spheroids. In MCF-7 spheroids, Vit-C-induced H2O2 production was higher, with a more pronounced decrease in the GSH/GSSG ratio, indicating greater susceptibility to oxidative stress-induced cell death. However, MDA-MB-231 spheroids exhibited a more severe cytotoxic response. Conclusions: This study reveals that Vit-C induces oxidative stress-mediated cell death in both non-aggressive and aggressive BC spheroids. Unlike traditional in vitro studies, this work provides novel insights into the response of two BC tumor subtypes to Vit-C, demonstrating its potential as a targeted common therapy for BC. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) seriously threatens women's health, and long noncoding RNAs (lncRNAs) are emerging as critical regulators of gene expression and play fundamental roles in TNBC. This study aimed to identify lncRNAs that represent effective targets for the early diagnosis or treatment of TNBC. Here, we utilized the TCGA database to analyze differentially expressed genes, and survival analysis and ROC curve analysis were also performed. Notably, we identified a novel lncRNA, AC112721.1, that is significantly overexpressed in TNBC and is associated with poor overall survival in TNBC patients. Loss- and gain-of-function experiments revealed that AC112721.1 significantly promoted cell proliferation and migration, suppressed cell apoptosis in vitro and inhibited tumorigenesis in vivo. Further study of the mechanisms underlying these effects revealed that AC112721.1 regulates the Ras pathway by directly binding to THBS1 protein and functions as a ceRNA by sponging miR-491-5p to increase the expression of C2CD2L, thereby influencing the progression of TNBC. Our findings indicate that AC112721.1 may represent a new biomarker for evaluating TNBC prognosis and treating TNBC. [ABSTRACT FROM AUTHOR]

Aims: The analgesic effect of ketamine in cancer pain remains controversial. This research investigates the role of ketamine in bone metastasis-induced cancer pain in breast cancer (BC) and its associated molecular network. Methods: BC cell lines MDA-MB-231 and ZR-75-1 were treated with ketamine and malignant behaviors were assessed through CCK-8, colony formation, and Transwell assays. To evaluate the pro-osteoclastic effect in vitro, BC cells were co-cultured with RAW 264.7 cells. Alterations in the expression of SRC proto-oncogene (SRC), early growth response 1 (EGR1), and cystatin E/M (CST6) were induced in BC cells using lentivirus. MDA-MB-231 cells were injected intracardially into nude mice to examine tumor bone metastasis in vivo. Molecular interactions between SRC and EGR1, as well as between EGR1 and CST6 were analyzed via immunoprecipitation and luciferase assays. Results: Ketamine treatment suppressed viability, proliferation, migration and invasiveness, epithelial-mesenchymal transition, and pro-osteoclastic effect in BC cells. Ketamine also reduced osteoclastogenesis and tumor bone metastasis burden and alleviated pain in nude mice. SRC was identified as a target of ketamine. Overexpression of SRC in BC cells blocked the effects of ketamine. SRC bound to the EGR1 promoter, suppressing EGR1 transcription, whereas EGR1 activated CST6 transcription. Either EGR1 or CST6 overexpression counteracted the function of SRC overexpression and decreased the viability of BC cells and their pro-osteoclastic effect in vitro and in vivo. Conclusion: This study demonstrates that ketamine alleviates BC cell-induced osteoclastogenesis and tumor bone metastasis by suppressing SRC and restoring the EGR1/CST6 axis. [ABSTRACT FROM AUTHOR]