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Pyroptosis is a gasdermin-mediated pro-inflammatory form of programmed cell death (PCD). Tumor necrosis factor-ɑ (TNF-ɑ) is an inflammatory cytokine, and some studies have shown that TNF-ɑ can cause pyroptosis of cells and exert anti-tumor effects. However, whether TNF-ɑ exerts anti-tumor effects on breast cancer cells by inducing pyroptosis has not been reported. In this study, to explore the impact of TNF-ɑ on pyroptosis in breast cancer cells, we treated MCF-7 cells with TNF-ɑ and found that TNF-ɑ induced cell death. Moreover, we observed that the dead cells were swollen with obvious balloon-like bubbles, which was a typical sign of pyroptosis. Further studies have found that the anti-tumor effect of TNF-ɑ on breast cancer cells in vitro was achieved through the canonical pyroptosis pathway. In addition, TNF-ɑ-induced pyroptosis in MCF-7 cells was associated with mitochondrial dysfunction, in which mitochondrial membrane potential was decreased and mitochondrial ROS production was increased. After inhibiting ROS production, the activation effect of TNF-ɑ on NLRP3/Caspase-1/GSDMD pathway was weakened, and the inhibitory effect of TNF-ɑ on the growth of MCF-7 cells in vitro was also decreased, further confirming the involvement of ROS in TNF-ɑ-induced pyroptosis. Overall, our study revealed a new mechanism by which TNF-ɑ exerts an anti-tumor effect by inducing pyroptosis in MCF-7 cells through the ROS/NLRP3/Caspase-1/GSDMD pathway, which may provide new therapeutic ideas for the treatment of breast cancer., (© 2024. The Author(s).)

Overexpression or activation of oncogenes or loss of tumor-suppressor genes can induce cellular senescence as a defense mechanism against tumor development, thereby maintaining cellular homeostasis. However, cancer cells can circumvent this senescent state and continue to spread. Myosin light chain kinase (MLCK) is downregulated in many breast cancers. Here we report that downregulation of MLCK in normal breast epithelial cells induces a senescence-associated secretory phenotype and stimulates migration. The reduction of MLCK results in increased p21 Cip1 expression, dependent on p53 and the AKT-mammalian target of rapamycin pathway. Subsequently, p21 Cip1 promotes the secretion of soluble ICAM-1, IL-1α, IL-6 and IL-8, thereby enhancing collective cell migration in a non-cell-autonomous manner. These findings provide new mechanistic insights into the role of MLCK in cellular senescence and cancer progression., (© 2024. The Author(s).)

In this study, a comprehensive methodology combining machine learning and statistical analysis was employed to investigate alterations in the metabolite profiles, including lipids, of breast cancer tissues and their subtypes. By integrating biological and machine learning feature selection techniques, along with univariate and multivariate analyses, a notable lipid signature was identified in breast cancer tissues. The results revealed elevated levels of saturated and monounsaturated phospholipids in breast cancer tissues, consistent with external validation findings. Additionally, lipidomics analysis in both the original and validation datasets indicated lower levels of most triacylglycerols compared to non-cancerous tissues, suggesting potential alterations in lipid storage and metabolism within cancer cells. Analysis of cancer subtypes revealed that levels of PC 30:0 were relatively reduced in HER2(-) samples that were ER(+) and PR(+) compared to those that were ER(-) and PR(-). Conversely, HER2(+) tumors, which were ER(-) and PR(-), exhibited increased concentrations of PC 30:0. This increase could potentially be linked to the role of Stearoyl-CoA-Desaturase 1 in breast cancer. Comprehensive metabolomic analyses of breast cancer can offer crucial insights into cancer development, aiding in early detection and treatment evaluation of this devastating disease., (© 2024. The Author(s).)

The medicinal plant Cannabis sativa L. (C. sativa) is currently being extensively studied to determine the full extent of its therapeutic pharmacological potential. Δ 9 -tetrahydocannabinol (THC) and cannabidiol (CBD) are the most thoroughly investigated compounds. We aimed to explore the anticancer activity of cannabinoids mixture isolated from the Lebanese C. sativa plant in ratios comparable to the local medicinal plant, to elucidate its mechanism of action in breast cancer cells in vitro. Cells were subjected to cytotoxicity assay, cell cycle analysis, Annexin V/PI dual staining, cell death ELISA, immunofluorescence, in addition to western blot analysis of apoptotic and autophagy markers. We further evaluated the anti-metastatic effect of cannabinoids on MDA-MB-231 using the scratch wound-healing, trans-well migration and invasion assays. Our results revealed the promising therapeutic benefits of CBD/THC on inhibiting the growth of breast cancer cells by promoting cellular fragmentation, phosphatidylserine translocation to the outer membrane leaflet and DNA fragmentation in both cell lines while inhibiting the motility of the triple negative breast cancer cells. In our study, CBD/THC mixture was found to exhibit a pro-apoptotic activity via the activation of the mitochondrial apoptotic pathway, independent from ROS production while also suggesting the activation of a caspase-dependent apoptotic pathway. Even though autophagy was altered upon exposure to the cannabinoid mixture, our data suggested that it is not the mechanism responsible of inducing cell death. In conclusion, our study demonstrates the promising therapeutic benefits of CBD and THC isolated from the Lebanese C. sativa plant on breast cancer cells in vitro., (© 2024. The Author(s).)

Copper-induced cell death is regulated through protein lipoylation, which is critical for gene expression and phenotypic regulation. Neverless, the role of Cuproptosis-related genes in breast cancer (BC) remains unknown. This study aimed to construct a prognostic signature based on the expression of Cuproptosis-related genes in order to guide the diagnosis and treatment for BC. Cuproptosis-related genes prognostic signature has ata of 1250 BC tissues and 583 normal breast tissues were obtained from The Cancer Genome Atlas (TCGA), Genotype Tissue Expression (GTEx), and GEO GSE65212. The prognostic signature was established and evaluated with nineteen Cuproptosis-related genes. A series of in silico analyses based on SLC31A1, included expression analysis, independent prognostic analysis, correlation analysis, immune-related analysis and survival analysis. Finally, a series of cell experiments (including quantitative real-time polymerase chain reaction and western blot), and mice experiments were applied to evaluate the impact of SLC31A1 on BC. Cuproptosis-related genes prognostic signature has good predictive promising for survival in BC patients. We discovered that SLC31A1SLC31A1 was overexpressed in BC and was its independent prognostic factor. High expression of the SLC31A1 was correlated with poor prognosis and immune infiltrating of BC. SLC31A1 expression is associated with immune, chemotherapeutic and targeted therapy outcomes in BC. The proliferation, migration, and invasiveness of Her2 + enriched BC cells were decreased by SLC31A1 knockdown, also resulting in a decrease in tumor volume in mouse model. SLC31A1 is a candidate biomarker or therapeutic target in precision oncology, with diagnostic and prognostic significance in BC., (© 2024. The Author(s).)

PI3K/AKT/mTOR pathway is implicated in breast cancer progression and recurrence. The identification of PIK3CA and AKT1 mutations and loss of PTEN serve as selection criterion for targeted therapies involving selective inhibitors. However, they do not consistently align with pathway activation, and high-cost determinations limit their routine application. PI3K-downstream epigenetic regulatory mechanisms broaden the alterations that amplify pathway activity and, consequently, sensitivity to selective inhibitors. In this retrospective observational study, conducted within a cohort of early-stage breast cancer patients, we determined phosphorylated ribosomal protein S6 (pS6) at Ser240/244 by immunohistochemistry as an indicator of PI3K pathway activation. Log-Rank test and Cox proportional hazards regression were used to analyze the clinical relevance of pS6, alone and together with clinicopathological variables, regarding recurrence-free survival. ROC curves and the area under the curves were used to evaluate the calibration and discrimination properties of uni- and multivariate models. Our results show that a high percentage of pS6 positive tumor cells was associated with an unfavorable prognosis in a cohort of 129 hormone receptor positive/HER2 negative breast cancer patients (Hazard Ratio = 5.92; Log-Rank p = 9.5e-08; median follow-up = 53 months). When assessed in combination with lymph node status, the predictive capacity was higher compared to both univariate models individually. In conclusion, pS6 could represent a novel independent marker for predicting recurrence risk in luminal breast cancer., (© 2024. The Author(s).)

Metastatic breast-cancer is one of the major causes of death, due to remaining dormant cancer cells for several years. Rac1 is upregulated with cancer and stay elevated throughout the metastatic pathway to regulate the formation of lamellipodia and filopodia. This work developed peptide FGDWS as novel inhibitor targeting Rac1-Tiam1 binding site by in-silico as it was found to be the strongest interacting peptide with Rac1 at the Tiam binding site. The binding and inhibition study of peptide with Rac1 was performed by Surface plasmon resonance and MTT assay, respectively. Cell-migration, apoptotic assay and western-blot in breast-cancer cells were performed with FGDWS and in combination with Doxorubicin (Dox). Tumor regression experiment was done with mice model. The strong binding of FGDWS with Rac1 and reduction of cell-viability were observed in breast-cancer cell-lines. The cell-migration was suppressed, and higher regression were obtained in synergy group. The apoptotic effect of FGDWS alone and with Dox were detected by annexin-V via activating caspase3/7. The tumor size was reduced by the treatment of FGDWS and more reduced in combinatorial effect. The combinatorial effect of FGDWS-Dox may enhance the treatment efficacy without side-effects., (© 2024. The Author(s).)

MicroRNAs are involved in breast cancer development and progression, holding potential as biomarkers and therapeutic targets or tools. The roles of miR-20a-5p, a member of the oncogenic miR-17-92 cluster, remain poorly understood in the context of breast cancer. In this study, we elucidate the role of miR-20a-5p in breast cancer by examining its associations with breast cancer risk factors and clinicopathological features, and its functional roles in vitro. Tissue microarrays from 313 CAMO cohort breast cancer surgical specimens were constructed, in situ hybridization was performed and miR-20a-5p expression was semiquantitatively scored in tumor stromal fibroblasts, and in the cytoplasm and nuclei of cancer cells. In vitro analysis of the effect of miR-20a-5p transfection on proliferation, migration and invasion was performed in three breast cancer cell lines. High stromal miR-20a-5p was associated with higher Ki67 expression, and higher odds of relapse, compared to low expression. Compared to postmenopausal women, women who were premenopausal at diagnosis had higher odds of high stromal and cytoplasmic miR-20a-5p expression. Cytoplasmic miR-20a-5p was significantly associated with tumor grade. In tumors with high cytoplasmic miR-20a-5p expression compared to low expression, there was a tendency towards having a basal-like subtype and high Ki67. In contrast, high nuclear miR-20a-5p in cancer cells was associated with smaller tumor size and lower odds of lymph node metastasis, compared to low nuclear expression. Transfection with miR-20a-5p in breast cancer cell lines led to increased migration and invasion in vitro. While the majority of our results point towards an oncogenic role, some of our findings indicate that the associations of miR-20a-5p with breast cancer related risk factors and outcomes may vary based on tissue- and subcellular location. Larger studies are needed to validate our findings and further investigate the clinical utility of miR-20a-5p., (© 2024. The Author(s).)

An established hallmark of cancer cells is metabolic reprogramming, largely consisting in the exacerbated glucose uptake. Adipocytes in the tumor microenvironment contribute toward breast cancer (BC) progression and are highly responsive to metabolic fluctuations. Metabolic conditions characterizing obesity and/or diabetes associate with increased BC incidence and mortality. To explore BC-adipocytes interaction and define the impact of glucose in such dialogue, Mammary Adipose-derived Mesenchymal Stem Cells (MAd-MSCs) were differentiated into adipocytes and co-cultured with ER + BC cells while exposed to glucose concentration resembling hyperglycemia or normoglycemia in humans (25mM or 5.5mM). The transcriptome of both cell types in co-culture as in mono-culture was profiled by RNA-Seq to define the impact of adipocytes on BC cells and viceversa (i), the action of glucose on BC cells, adipocytes (ii) and their crosstalk (iii). Noteworthy, we provided evidence that co-culture with adipocytes in a glucose-rich environment determined a re-program of BC cell transcriptome driving lipid accumulation, a hallmark of BC aggressiveness, promoting stem-like properties and reducing Tamoxifen responsiveness. Moreover, our data point out to a transcriptional effect through which BC cells induce adipocytes de-lipidation, paralleled by pluripotency gain, as source of lipids when glucose lowering occurs. Thus, modulating plasticity of peri-tumoral adipocytes may represent a key point for halting BC progression in metabolically unbalanced patients., (© 2024. The Author(s).)

Although the miR-183/182/96 cluster is overexpressed in breast cancer (BC), little is known about its role in the development of pre-carcinogenic lesions which harbor disrupted adherens junctions (AJ) and may promote BC. Here, we used microRNA and RNA sequencing data from The Cancer Genome Atlas (TCGA) Breast Cancer project to investigate the relationship between the miR-183/182/96 cluster and AJ signaling in early-stage BC. We found that all members of the cluster are significantly overexpressed in early-stage BC, the AJ signaling pathway is enriched for genes down-regulated in early-stage BC, and the AJ signaling pathway is enriched for experimentally validated targets of the miR-183/182/96 cluster. The expression of hsa-miR-182 correlates inversely with the mRNA expression of four of its target genes belonging to the AJ signaling pathway: WASF3, EGFR, MET, and CTNNA3. However, the correlations between hsa-miR-182 and AJ gene expression did not differ significantly between targets and non-targets of hsa-miR-182. This suggests that regulatory effects of microRNAs are less pronounced in cancer, as has been shown by other studies. Furthermore, WASF3, EGFR, and MET are oncogenes that tend to be upregulated in later BC stages, implying that the role of some AJ genes changes with different BC stages., (© 2024. The Author(s).)

Enhancing early-stage breast cancer detection requires integrating additional screening methods with current diagnostic imaging. Omics screening, using easily collectible serum samples, could serve as an initial step. Alongside biomarker identification capabilities, omics analysis allows for a comprehensive analysis of prevalent histological types-DCIS and IDC. Employing metabolomics, metallomics, and machine learning, could yield accurate screening models with valuable insights into organism responses. Serum samples of confirmed breast cancer patients were utilized to analyze metabolite and metal ion profiles, using two distinct analysis methods, proton NMR for metabolomics and ICP-OES for metallomics. The resulting responses were then subjected to discriminant analysis, progression biomarker exploration, examination of correlations between patients' metabolites and metal ions, and the impact of age and menopause status. Measured NMR spectra and metabolite relative integrals were used to achieve statistically significant discrimination through MVA between breast cancer and control groups. The analysis identified 24 metabolites and 4 metal ions crucial for discrimination. Furthermore, four metabolites were associated with disease progression. Additionally, there were important correlations and relationships between metabolite relative integrals, metal ion concentrations, and age/menopausal status subgroups. Quantified relative integrals allowed for discrimination between studied subgroups, validated with a holdout set. Feature importance and statistical analysis for metabolomics and metallomics extracted a set of common entities which in combination provides valuable insights into ongoing molecular disturbances and disease progression., (© 2024. The Author(s).)

ER+/HER2- breast cancer is a common subtype of breast cancer. This study aimed to evaluate the prognostic value of ER-to-PR difference (EPD) in ER+/HER2- early breast cancer (EBC). A retrospective cohort study was conducted, including 3,340 ER+/HER2- EBC patients, divided into a training cohort of 2,873 patients and a validation cohort of 467 patients. The optimal EPD cutoff value for stratifying patients was determined using X-tile. Additionally, the prognostic value of EPD, when combined with other clinicopathological factors, was assessed using the Cox proportional hazards model and five traditional machine learning methods. The optimal cutoff value for EPD was determined as 10%, categorizing patients into EPD-low (ER-PR ≤ 10%) and EPD-high (ER-PR > 10%) expression groups. Patients with EPD-high tumors exhibited a poorer prognosis compared to those with EPD-low tumors. In the multivariate Cox model, EPD was identified as an independent prognostic factor for disease-free survival (DFS) (HR: 1.496, P = 0.004). Integrating EPD with clinicopathological parameters into a predictive model effectively predicts DFS in ER+/HER2- EBC patients. In the most effective CoxPH model, the area under the curve (AUC) values for predicting 3-year, 5-year, and 7-year DFS were 0.718, 0.702, and 0.701, respectively, in the WCH cohort, and 0.770, 0.739, and 0.743, respectively, in the FUSCC cohort. EPD may serve as a novel prognostic marker, allowing for the identification of a population with a poor prognosis in ER+/HER2- EBC, thereby aiding clinical decision-making., (© 2024. The Author(s).)

Breast cancer remains a leading cause of mortality among women worldwide, with drug resistance driven by transcription factors and mutations posing significant challenges. To address this, we present ResisenseNet, a predictive model for drug sensitivity and resistance. ResisenseNet integrates transcription factor expression, genomic markers, drugs, and molecular descriptors, employing a hybrid architecture of 1D-CNN + LSTM and DNN to effectively learn long-range and temporal patterns from amino acid sequences and transcription factor data. The model demonstrated exceptional predictive accuracy, achieving a validation accuracy of 0.9794 and a loss value of 0.042. Comprehensive validation included comparisons with state-of-the-art models and ablation studies, confirming the robustness of the developed architecture. ResisenseNet has been applied to repurpose existing anticancer drugs across 14 different cancers, with a focus on breast cancer. Among the malignancies studied, drugs targeting Low-grade Glioma (LGG) and Lung Adenocarcinoma (LUAD) showed increased sensitivity to breast cancer as per ResisenseNet's assessment. Further evaluation of the predicted sensitive drugs revealed that 14 had no prior history of anticancer activity against breast cancer. These drugs target key signaling pathways involved in breast cancer, presenting novel therapeutic opportunities. ResisenseNet addresses drug resistance by filtering ineffective compounds and enhancing chemotherapy for breast cancer. In vitro studies on sensitive drugs provide valuable insights into breast cancer prognosis, contributing to improved treatment strategies., (© 2024. The Author(s).)

Breast Cancer (BC) is the most common cause of cancer-associated deaths in females worldwide. Despite advancements in BC treatment driven by extensive characterization of its molecular hallmarks, challenges such as drug resistance, tumor relapse, and metastasis persist. Therefore, there is an urgent need for alternative treatment approaches with multi-modal efficacy to overcome these hurdles. In this context, natural bioactives are increasingly recognized for their pivotal role as anti-cancer compounds. This study focuses on predicting molecular targets for key herbal phytoconstituents-gallic acid, piperine, quercetin, resveratrol, and beta-sitosterol-present in the polyherbal formulation, Krishnadi Churna. Using an in-silico network pharmacology model, key genes were identified and docked against these marker compounds and controls. Mammary carcinoma emerged as the most significant phenotype of the putative targets. Analysis of an online database revealed that out of 135 predicted targets, 134 were mutated in breast cancer patients. Notably, ESR1, CYP19A1, and EGFR were identified as key genes which are known to regulate the BC progression. Docking studies demonstrated that the herbal phytoconstituents had similar or better docking scores than positive controls for these key genes, with convincing protein-ligand interactions confirmed by molecular dynamics simulations, MM/GBSA and free energy landscape (FEL) analysis. Overall, this study highlights the predictive potential of herbal phytoconstituents in targeting BC genes, suggesting their promise as a basis for developing new therapeutic formulations for BC., (© 2024. The Author(s).)

Hormone receptor-positive breast cancer (BC) is the most prevalent subtype of BC and is generally correlated with a favorable prognosis. This study aimed to determine the incidence and survival trends among women diagnosed with hormone receptor-positive BC between 1990 and 2019. Female patients with hormone receptor-positive BC for calendar years 1990-2019 were obtained from the Surveillance, Epidemiology, and End Results (SEER) database and categorized into six diagnostic groups according to the year of diagnosis. Age-adjusted incidence rates (IRs) were calculated using joinpoint regression. We used the Kaplan-Meier method and multivariate Cox regression analyses to determine the association between diagnostic groups, and overall survival (OS) and BC-specific survival (BCSS). The final analysis included 370,729 women, among whom 37,943 (10.2%), 49,266 (13.3%), 55,652 (15.0%), 64,451 (17.4%), 77,127 (20.8%), and 86,290 (23.3%) were diagnosed between 1990 and 1994, 1995-1999, 2000-2004, 2005-2009, 2010-2014, and 2015-2019, respectively. Within the overall cohort, IRs gradually increased from 70 per 100,000 in 1990 to 113 per 100,000 in 2019 (average annual percent change, 1.59%; 95% CI, 1.18-1.99). Multivariate Cox regression analysis revealed that the survival outcomes gradually improved over nearly three decades among hormone receptor-positive BC patients, with a 0.8% and 1.3% decrease in risk for all-cause and BC-specific mortality each year, respectively. Compared to 1990-1994, hormone receptor-positive BC patients diagnosed in 2015-2019 had a 22% lower risk of all-cause death (hazard ratio [HR], 0.78; 95% CI, 0.76-0.81) and a 27% lower risk of BC-specific death (HR, 0.73; 95% CI, 0.70-0.76). The development of treatment strategies within the past three decades, especially endocrine therapy, may contribute to the continuous improvement of clinical outcomes in patients with hormone receptor-positive BC., (© 2024. The Author(s).)

Neoadjuvant endocrine therapy (NET) for hormone receptor-positive (HR+) breast cancer might be as effective as chemotherapy, with a better toxicity profile. Blocking a crucial process such as angiogenesis with sunitinib may have a synergistic effect with NET. We aimed to assess the efficacy and safety of neoadjuvant sunitinib plus exemestane in early-stage HR+/HER2-negative breast cancer. In this phase I/II study, postmenopausal women with HR+/HER2- stage II-III breast cancer received neoadjuvant exemestane at conventional dose of 25mg plus sunitinib in a 3 + 3 design at 25mg (3/1weeks scheme) or 37.5mg continuous dose, for 6 months. Coprimary endpoints were the recommended dose of sunitinib combined with exemestane and objective response. Secondary endpoints included safety and biomarkers of early response. For 15 months, 18 patients were enrolled, 15 at sunitinib 25mg and 3 at 37.5mg. Median age was 73, 77% of patients had T2 tumors and 67% node-positive disease. The most common grade 2 toxicity was asthenia (44%), as was hypertension (22%) for grade 3. No grade 4-5 were reported. Twelve patients (66%) achieved an objective response. VEGFR-2 levels significantly decreased after one month of treatment. Differential gene expression analysis showed downregulation of ESR1, PGR and NAT1 in post-treatment samples and upregulation of EGFR, MYC, SFRP1, and FOXC1. PAM50 analysis on 83% of patients showed a prevalence of luminal A subtype, both in pre-treatment (63.6%) and post-treatment tumors (54.5%). Sunitinib plus exemestane was associated with substantial yet reversible toxicities, providing safety, efficacy and biological impact insights of combining an antiangiogenic drug with hormone therapy in early-stage breast cancer.Trial registration: Registered with ClinicalTrials.gov, NCT00931450. 02/07/2009., (© 2024. The Author(s).)

The objective of this study was to investigate the correlation between Rab10 (GTP binding protein RAB10), TLR4 (Toll-like receptor 4), and NF-κB (nuclear factor kappa-B) levels and therapeutic effects in peripheral blood of patients with breast cancer after surgery. The study included 160 patients with stage I-III breast cancer who underwent surgical treatment at our hospital's Department of Breast Surgery and Oncology between January 2021 and June 2021. ELISA was used to assess Rab10, TLR4, and NF-κB levels in peripheral blood. Based on their levels of Rab10, TLR4, and NF-κB in peripheral blood, participants were categorized into two groups: the low marker expression group (72 participants with relatively low expression of Rab10, TLR4, and NF-κB: Rab10<2.0ng/ml; TLR4<2.75ng/ml; NF-κB<3.5ng/ml) and the high marker expression group (88 participants with relatively high expression: Rab10 ≥ 2.0 ng/ml; TLR4 ≥ 2.75ng/ml; NF-κB ≥ 3.5ng/ml). All participants provided informed consent to participate the study. The baseline data of the two groups of patients, the presence or absence of lymph node metastasis and recurrence within 3 years after surgery, as well as the survival status within 3 years after surgery (including median overall survival and median progression-free survival) were statistically analyzed. The expressions of Rab10, TLR4, and NF-κB in the peripheral blood of patients were detected through enzyme-linked immunosorbent assay (ELISA). Kendall's tau-b correlation analysis was conducted to examine the relationship between the expressions of Rab10, TLR4, and NF-κB and the therapeutic effects outcomes. The levels of Rab10, TLR4, and NF - κ B in peripheral blood of the high marker expression group were higher than those of the low marker expression group (Rab10: 1.87 ± 0.18 vs. 3.15 ± 0.24 ng/ml; TLR4: 2.17 ± 0.20 vs. 3.26 ± 0.25 ng/ml); NF-κB: 2.68 ± 0.27 vs. 4.63 ± 0.30 ng/ml; P < 0.05). Analyzing the relationship between patient staging and Rab10, TLR4, and NF - κ B expression, the number of patients in high marker expression group III-IV increased compared to the low marker expression group (54.55% vs. 36.12%; P < 0.05), while the number of patients in high marker expression group I-II decreased compared to the low marker expression group (45.45% vs. 63.88%; P < 0.05). It was found that the number of patients with no recurrence or metastasis in the high marker expression group decreased compared to the low marker expression group (56.81% vs. 73.61%; P < 0.05), while the number of patients with recurrence or metastasis in the high marker expression group increased compared to the low marker expression group (43.19% vs. 26.39%; P < 0.05). The median overall survival and median progression free survival in the high marker expression group were shorter than those in the low marker expression group (median overall survival: 21.45 ± 2.68 months vs. 28.38 ± 3.44 months; median progression free survival: 15.25 ± 2.37 vs. 20.72 ± 2.58 months; P < 0.05). Kendall's tau-b correlation indicated a positive correlation between the expressions of Rab10, TLR4, and NF-κB and a poor therapeutic effects (P < 0.05), suggesting that elevated levels of Rab10, TLR4, and NF-κB may lead to a worsened therapeutic effects. There is a significant correlation between the presence of Rab10, TLR4, and NF-κB in the peripheral blood of breast cancer patients. Elevated levels of Rab10, TLR4, and NF-κB are linked to an increased risk of recurrence, metastasis, reduced overall survival, and progression-free survival., (© 2024. The Author(s).)

Breast cancer metastasis is associated with a poor prognosis and a high rate of mortality. Cathepsin L (CTSL) is a lysosomal cysteine protease that promotes tumor metastasis by degrading the extracellular matrix. Gene set enrichment analysis revealed that CTSL expression was higher in tumorous than in non-tumorous tissues of breast cancer patients and that high-level CTSL expression correlated positively with the epithelial-mesenchymal transition. Therefore, we hypothesized that inhibiting CTSL activity in tumor cells would prevent metastasis. In this study, we characterized the inhibitory activity of SnuCalCpI15, the I29 domain of a CTSL-like cysteine protease from Calotropis procera R. Br., and revealed that the propeptide stereoselectively inhibited CTSL in a reversible slow-binding manner, with an inhibitory constant (K i ) value of 1.38 ± 0.71 nM, indicating its potency as an exogenous inhibitor in anti-cancer therapy. SnuCalCpI15 was localized intracellularly in MDA-MB-231 breast cancer cells and suppressed tumor cell migration and invasion. These results demonstrate the potential of SnuCalCpI15 as a novel agent to prevent breast cancer metastasis., (© 2024. The Author(s).)

Compartmentalization and differential distribution of proteins within a cell maintain cellular function and viability. CapG is a gelsolin-related actin-binding protein that distributes in steady state diffusively throughout cytoplasm and cell nucleus. To detect changes in CapG's nucleocytoplasmic shuttling in response to external stimuli on the single cell level, we established repeated FRAP experiments of one and the same breast cancer cell. With this experimental set up, we found that ATP-depletion reversibly decreased CapG's shuttling into the cell nucleus. The addition of epidermal growth factor (EGF) increased CapG's nuclear shuttling within minutes. Serum-starvation doubled the number of breast cancer cells from 40 to 80% displaying increased CapG shuttling in response to EGF. Testing five different potential CapG phosphorylation sites, we found that serine 70 mediates the increase in CapG's nuclear shuttling triggered by EGF. Thus, repeated FRAP of CapG in the cell nucleus can be used as functional readout of signaling cascades in the same single live breast cancer cell., (© 2024. The Author(s).)

Distinguishing between pathologic complete response and residual cancer after neoadjuvant chemotherapy (NAC) is crucial for treatment decisions, but the current imaging methods face challenges. To address this, we developed deep-learning models using post-NAC dynamic contrast-enhanced MRI and clinical data. A total of 852 women with human epidermal growth factor receptor 2 (HER2)-positive or triple-negative breast cancer were randomly divided into a training set (n = 724) and a validation set (n = 128). A 3D convolutional neural network model was trained on the training set and validated independently. The main models were developed using cropped MRI images, but models using uncropped whole images were also explored. The delayed-phase model demonstrated superior performance compared to the early-phase model (area under the receiver operating characteristic curve [AUC] = 0.74 vs. 0.69, P = 0.013) and the combined model integrating multiple dynamic phases and clinical data (AUC = 0.74 vs. 0.70, P = 0.022). Deep-learning models using uncropped whole images exhibited inferior performance, with AUCs ranging from 0.45 to 0.54. Further refinement and external validation are necessary for enhanced accuracy., (© 2024. The Author(s).)

Reprogrammed glucose metabolism is considered as the hallmark of cancer with therapeutic implications. Phytocompounds have potential to inhibit cancer metabolism. Here, we tested the ability of Withaferin A (WA), a withanolide derived from Withania somnifera, in modulating cancer metabolism. The assessed effect of WA on aerobic glycolysis in breast cancer cell lines showed that WA decreases the glucose uptake, lactate production and ATP generation by inhibiting the expression of key glycolytic enzymes i.e., GLUT1, HK2 and PKM2. We also identified that WA induced inhibition of cancer glycolysis by targeting c-myc as validated by silencing experiments followed by metabolic readouts. Decreased glycolysis resulted in reduced cell viability, biomass and colony forming ability of breast cancer cells. To further validate our in vitro findings in breast cancer patients, we analyzed 90 metabolic pathways in ~ 2000 breast tumors and observed that glycolysis is the most deregulated pathway in breast tumors. Deregulated glycolysis also predicted poor prognosis in breast cancer patients. In addition, patient data showed correlation between c-myc expression and glycolytic deregulation in breast cancer. Taken together, our results highlight the role of WA in inhibiting breast cancer metabolism via c-myc/glycolysis axis., (© 2024. The Author(s).)

Tamoxifen (TAM) resistance is a major challenge in treating oestrogen receptor-positive (ER+) breast cancers. It is possible that the H 2 S synthase cystathionine-γ-lyase (CSE), which has been previously shown to promote tumour growth and metastasis in other cancer cells, is involved in this resistance. Therefore, we investigated CSE's role and potential mechanisms in TAM-resistant breast cancer cells. First, we examined the effect of CSE expression on TAM sensitivity and resistance in MCF7 (breast cancer) cells. The findings revealed that CSE was directly associated with TAM sensitivity and involved in TAM resistance in ER+ breast cancer cells, indicating that it may be useful as a biomarker. Next, we wanted to determine the molecular mechanism of CSE's role in TAM resistance. Using cell migration, co-immunoprecipitation, western blotting, and cell viability assays, we determined that the CSE/H2S system can affect the expression of PPARγ by promoting the sulfhydrylation of PPARγ, which regulates the transcriptional activity of ACSL1. ACSL1, in turn, influences STAT3 activation by affecting the phosphorylation, palmitoylation and dimerization of STAT3, ultimately leading to the development of TAM resistance in breast cancer. Finally, we examined the effect of CSE inhibitors on reducing drug resistance to determine whether CSE may be used as a biomarker of TAM resistance. We observed that the novel CSE inhibitor I194496 can reverse TAM resistance in TAM-resistant breast cancer via targeting the PPARγ/ACSL1/STAT3 signalling pathway. Overall, our data indicate that CSE may serve as a biomarker of TAM resistance and that the CSE inhibitor I194496 is a promising candidate for combating TAM resistance., (© 2024. The Author(s).)

Plasticity is an inherent feature of cancer stem cells (CSCs) and regulates the balance of key processes required at different stages of breast cancer progression, including epithelial-to-mesenchymal transition (EMT) versus mesenchymal-to-epithelial transition (MET), and glycolysis versus oxidative phosphorylation. Understanding the key factors that regulate the switch between these processes could lead to novel therapeutic strategies that limit tumor progression. We found that aldehyde dehydrogenase 1A3 (ALDH1A3) regulates these cancer-promoting processes and the abundance of the two distinct breast CSC populations defined by high ALDH activity and CD24 - CD44 + cell surface expression. While ALDH1A3 increases ALDH + breast cancer cells, it inversely suppresses the CD24 - CD44 + population by retinoic acid signaling-mediated gene expression changes. This switch in CSC populations induced by ALDH1A3 was paired with decreased migration but increased invasion and an intermediate EMT phenotype. We also demonstrate that ALDH1A3 increases oxidative phosphorylation and decreases glycolysis and reactive oxygen species (ROS). The effects of ALDH1A3 reduction were countered with the glycolysis inhibitor 2-deoxy-D-glucose (2DG). In cell culture and tumor xenograft models, 2DG suppresses the increase in the CD24 - CD44 + population and ROS induced by ALDH1A3 knockdown. Combined inhibition of ALDH1A3 and glycolysis best reduces breast tumor growth and tumor-initiating cells, suggesting that the combination of targeting ALDH1A3 and glycolysis has therapeutic potential for limiting CSCs and tumor progression. Together, these findings identify ALDH1A3 as a key regulator of processes required for breast cancer progression and depletion of ALDH1A3 makes breast cancer cells more susceptible to glycolysis inhibition., (© 2024. The Author(s).)

HER2-positive (HER2+) breast cancer accounts for 20-30% of all breast cancers. Although trastuzumab has significantly improved the survival of patients with HER2+ breast cancer, more than 70% of patients develop drug resistance within one year of treatment. Differential-gene-expression analysis of trastuzumab-sensitive and resistant HER2+ breast cancer cell lines from GSE15043 was performed to identify the biomarkers associated with trastuzumab resistance. Differential biomarker expression was confirmed in FFPE tissues collected from clinical HER2+ breast cancer tumor samples that were sensitive or resistant to trastuzumab treatment. UGT1A7, a member of the uronic acid transferase family, was associated with trastuzumab resistance. UGT1A7 expression was downregulated in trastuzumab-resistant tumor tissues and in a cell line that developed trastuzumab resistance (BT474TR). Overexpressing UGT1A7 in BT474TR restored their sensitivity to trastuzumab treatment, whereas downregulating UGT1A7 expression in parental cells led to trastuzumab resistance. Importantly, UGT1A7 localized to the endoplasmic reticulum and altered stress responses. Furthermore, downregulating UGT1A7 expression promoted epithelial-to-mesenchymal transition (EMT) by affecting TWIST, SNAIL, and GRP78 expression and the AMP-activated protein kinase signaling pathway, thus contributing to trastuzumab resistance. This study demonstrated the important role and novel mechanisms of UGT1A7 in tumor responses to trastuzumab. Low UGT1A7 expression plays an important role in EMT and contributes to trastuzumab resistance. UGT1A7 has the potential to be developed as a biomarker for identifying patients who are resistant to trastuzumab treatment., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

An increasing number of studies indicate that long noncoding RNAs (lncRNAs) play important roles in tumour proliferation, migration and other vital processes and are expected to become novel biomarkers for early cancer screening. The expression of the lncRNA NBR2 (adjacent breast cancer suppressor BRCA1) has been found to decrease in several cancer types. However, it is still unknown whether the lncRNA NBR2 is involved in breast cancer and autophagy. According to the Kaplan-Meier plotter survival curve analysis, the survival rate of the group with high lncRNA-NBR2 expression was higher than that of the group with low lncRNA-NBR2 expression. The suppression of cancer cell proliferation, invasion and migration by the lncRNA NBR2 has been demonstrated, suggesting that this lncRNA is involved in the development and progression of cancer. Our subsequent study revealed that the lncRNA NBR2 inhibited autophagy in breast cancer cells, and that starvation conditions enhanced this inhibitory effect. Moreover, this lncRNA changed the proliferation ability of breast cancer cells by affecting protective autophagy. The aim of this study was to investigate the link between starvation and lncRNAs by evaluating changes in autophagy-related proteins, cell proliferation and other biological processes. Together, these studies provide strategies for the early screening of breast cancer and suggest that starvation therapy can be used as a new approach for the treatment of cancer., (© 2024. The Author(s).)

The extra domain B splice variant of fibronectin (EDB-FN), which is overexpressed in several cancers, is an approved diagnostic and therapeutic target of cancers. The aim of this study was to evaluate the EDB-FN-targeting peptide EDBp as a noninvasive imaging modality for molecular imaging of breast cancer in mice. Western blot, flow cytometry and immunofluorescence were used to assess the expression level of EDB-FN and its binding to EDRp in MCF7, SKBR3, 4T1, EMT6, MDA-MB-231 and MDA-MB-453 cells. Establishment MDA-MB-231-luc cells-based subcutaneous tumor model mice or pulmonary metastasis model mice. The EDRp molecular probes to perform fluorescent probes for near-infrared fluorescence (NIRF)·and PET imaging of model mice. Our results demonstrate that EDBp-Cy5 had a strong binding ability to the MDA-MB-231 cells and exhibited specific tumor accumulation in MDA-MB-231 subcutaneous and pulmonary metastasis model mice. Importantly, the EDBp peptide-based radiotracer [ 18 F]-AlF-NOTA-EDBp provided excellent diagnostic value for positron emission tomography (PET) imaging of breast cancer, especially in subcutaneous model mice. The uptake of [ 18 F]-AlF-NOTA-EDBp in subcutaneous tumors (6.53 ± 0.89%, ID/g) was unexpectedly higher than that in the kidney (4.96 ± 0.20, %ID/g). The high tumor uptake of these probes in mice suggests their potential for application in imaging of EDB-FN-positive breast cancer for disease staging of regional and distant metastases., (© 2024. The Author(s).)

Vitamin D 3 (VD) is known for its immunomodulatory and anticancer effects. This study aimed to characterize tumor-associated macrophages (TAMs) in breast cancer (BC) and assess the influence of VD and its active metabolite, calcitriol, on their polarization. TAMs were isolated from BC patients and characterized. Monocytes were differentiated into macrophage classes (M0, M1, M2a, M2c) and treated ex vivo with calcitriol. The expression of VD-related proteins in tumor tissue was correlated with TAMs and monocyte-derived macrophages (MDMs) characteristics. TAM expression of CD200R, CD204, CD80, HLA-DR, and CD44 was negatively correlated with CYP27B1 in selected patient groups. Patients with high CYP27B1 tumor expression showed significantly lower CD200R, CD204, and CD44 expression. In patients with normal VD levels and premenopausal, CD80 expression in M2a and M2c MDMs (control, untreated ex vivo with calcitriol) was negatively correlated with plasma VD. Calcitriol reduced HLA-DR during MDM differentiation in all patients; CD80 decrease significantly except in patients with normal VD levels or metastasis. Calcitriol also decreased CD163 expression. The decrease in both M1 and M2 macrophage markers by calcitriol or their negative correlation with CYP27B1 indicate the modulatory, but rather anticancer activity of VD. The intensity of these effects was the strongest in postmenopausal patients and those without metastases., (© 2024. The Author(s).)

SASH1 (SAM and SH3 domain containing 1) has been increasingly reported as a tumor suppressor gene. However, there is limited research on the role of SASH1 in breast cancer. This manuscript aims to investigate the mechanism of SASH1 in the occurrence, development, and prognosis of breast cancer. Firstly, we obtained RNA-sequencing data of the tumors from the Genomic Data Commons data portal website, along with the corresponding clinical information of patients. Pan-cancer analysis was performed to analyze the expression of SASH1 across all tumors. Univariate Cox regression analysis was used to assess the correlation between SASH1 expression and the prognosis of breast cancer patients. Then, immunohistochemistry was utilized to evaluate the expression levels of SASH1, p-Akt, p-PI3K, and p-mTOR in breast cancer tissue. Finally, a cell assay was employed to analyze the impact of SASH1 on the proliferation and invasion of breast cancer cells (MDA-MB-231). The results revealed that SASH1 expression is decreased in BRCA, LUSC, LUAD, CESC, ESCA, and COAD. Meta-analysis also found that SASH1 is downregulated in most tumor tissues, and the expression level of SASH1 in breast cancer was significantly lower than that in the control group (OR = 0.14, 95% CI = 0.08-0.25; P < 0.001). Further experimental validation showed that SASH1 expression is significantly downregulated in breast cancer tissue (38.33%, 23/60), and the overexpression of SASH1 can inhibit the proliferation and invasion of breast cancer cells accompanied by the suppression of PI3K-Akt-mTOR signaling pathway. Additionally, SASH1 overexpression can improve OS and RFS of breast cancer patients., (© 2024. The Author(s).)

A novel core-shell nanocarrier system has been designed for co-delivery of a small anticancer drug, docetaxel (DTX) and tumor suppressor (TS) miR-34a named as Exo(PAN 34a+DTX ). The core is formed by pH dependent polyamine salt aggregates (PSA) containing both the payloads and the shell is formed by RAW 264.7 cell derived exosomal fragments. Herein, phosphate driven polyallylamine hydrochloride (PAH, MW:17,500 Da) PSA was formed in presence of miR-34a and DTX to form PAN 34a+DTX . The formulation exhibited pH dependent DTX release with only 33.55 ± 2.12% DTX release at pH 7.2 and 75.21 ± 1.8% DTX release till 144 h at pH 5.5. At 1.21 molar ratio of phosphate to the amine (known as R value), efficient complexation of miR-34a (3.6 μM) in the PAN particles was obtained. PAN 34a+DTX demonstrated particle size (163.86 ± 12.89 nm) and zeta-potential value of 17.53 ± 5.10 mV which upon exosomal fragment layering changed to - 7.23 ± 2.75 mV which is similar to the zeta-potential of the exosomal fragments, i.e., - 8.40 ± 1.79 mV. The final formulation Exo(PAN 34a+DTX ), loaded with 40 ng/mL DTX and 50 nM miR-34a exhibited 48.20 ± 4.59% cytotoxicity in triple negative breast cancer (TNBC) cells, 4T1. Co-localization of CM-DiI (red fluorescence) stained exosomal fragments and FAM-siRNA (green fluorescence) in the cytoplasm of 4T1 cells after 6 h of Exo(PAN FAM ) treatment confirmed the efficiency of the designed system to co-deliver two actives. Exo(PAN 34a+DTX ) also reduced BCL-2 expression (target gene for miR-34a) by 8.98 folds in comparison to free DTX confirming promising co-delivery and apoptosis inducing effect of Exo(PAN 34a+DTX ) in 4T1., (© 2024. The Author(s).)

The phosphatase and tensin homolog (PTEN) gene acts as a tumor suppressor by regulating the PI3K/AKT pathway, crucial for cell growth and survival. Mutations or loss of PTEN are common in breast cancer, leading to uncontrolled cell growth. Understanding PTEN's role is vital for targeted therapies. 276 formalin-fixed paraffin-embedded (FFPE) breast cancer tissue blocks from 2012 to 2016 were analyzed for PTEN expression. Immunohistochemistry was performed to identify and assess tumor related clinicopathological characteristics as well as patient demographics. These were statistically matched with PTEN expression. Only 27.5% of the breast cancer tumors were PTEN-positive. PTEN expression correlated significantly with smaller tumor size, lower tumor grade, positive estrogen and progesterone receptor status, and favorable/unfavorable Ki67 status (p < 0.001). No significant association was found with vascular invasion, histologic type, age, HER2 status, staging, or lymph node involvement (p > 0.05). The study confirms PTEN's association with favorable clinicopathological features in breast cancer, supporting its role as a prognostic marker. These findings underscore the importance of PTEN in breast cancer biology and its potential as a therapeutic target. Furthermore these findings confirm the prevalence of advanced stage and aggressive breast cancer tumors in Ghana., (© 2024. The Author(s).)

The individual variation of carcinogenesis and drug response is influenced by the absorption, distribution, metabolism, and excretion (ADME) of drugs. The utilization of signatures derived from ADME-related genes holds potential for predicting prognosis and treatment response across diverse cancer types. Further investigation is required to completely understand the role of ADME-associated genes in breast cancer. A signature was constructed through the application of a least absolute shrinkage and selection operator regression model, employing prognostic differentially expressed genes found in both cancer tissue and normal tissue. To assess the robustness of the signature, verification analyses were carried out. RT-qPCR was utilized for the validation of gene expression related to risk. Subsequently, a nomogram was developed to enhance the clinical utility of our prognostic tool. The ADME signature, comprising four genes, was established and exhibited a robust association with the prognoses of individuals diagnosed with breast cancer. The nomogram was created by fusing the clinicopathological characteristics with the ADME signature. The ADME signature demonstrated remarkable superiority when compared to the performance of the other individual predictors. Additionally, the analysis of the immune microenvironment revealed that the ImmuneScores of the low-risk group were elevated. The variation in both the infiltration of immune cells and the expression of immune-related genes in the tissues differed among the two groups. For patients with breast cancer, the utilization of ADME signatures as biomarkers presents a significant reference point for prognosis and individualized treatment strategies., (© 2024. The Author(s).)

In this study, the necessity of radiotherapy (RT) for hormone receptor-negative older breast cancer patients after breast-conserving surgery (BCS) was investigated. The data of hormone receptor-negative invasive breast cancer patients who underwent BCS were extracted from the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2015. All patients were separated into two groups, namely, the RT group and the no radiotherapy (No RT) group. The 3- and 5-year overall survival (OS) and cancer-specific survival (CSS) rates were compared between the No RT and RT groups after propensity score matching (PSM). The nomograms for predicting the survival of patients were constructed from variables identified by univariate or multivariate Cox regression analysis. A total of 2504 patients were enrolled in the training cohort, and 630 patients were included in the validation cohort. After PSM, 738 patients were enrolled in the No RT group and RT group. We noted that RT can improve survival in hormone receptor-negative older breast cancer patients who undergo BCS. Based on the results of multivariate Cox analysis, age, race, tumour grade, receipt of RT and chemotherapy, pathological T stage, N status, M status and HER2 status were linked to OS and CSS for these patients, and nomograms for predicting OS and CSS were constructed and validated. Moreover, RT improved OS and CSS in hormone receptor-negative older breast cancer patients who underwent BCS. In addition, the proposed nomograms more accurately predicted OS and CSS for hormone receptor-negative older breast cancer patients after BCS., (© 2024. The Author(s).)

High tumor's lactate level directly associates with high tumor growth, metastasis, and patients' poor prognosis. Therefore, many studies have focused on the decrease of tumor's lactate as a novel cancer treatment. In the present study for the first time, a strictly anaerobic lactate-fermenting bacterium, Veillonella parvula, was employed for the decrease of tumor's lactate level. At first, 4T1 breast tumor-bearing BALB/c mice were administered with 10 6 V. parvula bacteria intravenously, orally, intraperitoneally, and intratumorally. Then, the bacteria biodistribution was evaluated. The best administration route according to tumor colonization was selected and its safety was assessed. Then, the therapeutic effect of V. parvula administration through the best route was investigated according to 4T1 murine breast tumor's growth and metastasis in vivo. In addition, histopathological and immunohistochemistry evaluations were done to estimate microscopic changes at the inner of the tumor and tumor's lactate level was measured after V. parvula administration. V. parvula exhibited considerable tumor-targeting and colonization efficacy, 24 h after intravenous administration. Normal organs were free of the bacteria after 72 h and no side effect was observed. Tumor colonization by V. parvula significantly decreased the tumors' lactate level for about 46% in comparison with control tumors which caused 44.3% and 51.6% decline (P < 0.05) in the mean tumors' volume and liver metastasis of the treatment group in comparison with the control group, respectively. The treatment group exhibited 35% inhibition in the cancer cell proliferation in comparison with the control according to the Ki-67 immunohistochemistry staining. Therefore, intravenous administration of V. parvula is a tumor-specific and safe treatment which can significantly inhibit tumors' growth and metastasis by decreasing the tumor lactate level., (© 2024. The Author(s).)

Metastasis accounts for almost 90% of breast cancer-related fatalities, making it frequent malignancy and the main reason of tumor mortality globally among women. LSD1 is a histone demethylase, which plays an important role in breast cancer. In order to explore the effect of LSD1 on invasion and migration of breast cancer, we treated breast cancer cells with MCF7 and T47D exosomes knocked down by LSD1, and the invasion and migration of breast cancer cells were significantly enhanced. This phenomenon indicates that LSD1 can inhibit the invasion and migration of breast cancer cells. miR-1290 expression was downregulated in LSD1 knockdown MCF7 exosomes. By analyzing the database of miR-1290 target gene NAT1, we verified that miR-1290 could regulate the expression of NAT1. These data provide fresh insights into the biology of breast cancer therapy by demonstrating how the epigenetic factor LSD1 stimulates the breast cancer cells' invasion and migration via controlling exosomal miRNA., (© 2024. The Author(s).)

Cytokine-induced apoptosis inhibitor 1 (CIAPIN1) is a protein that regulates apoptosis and programmed cell death. This research aims to evaluate its potential role in inhibiting breast cancer cell proliferation, migration, and glycolysis and uncover its underlying molecular mechanism. We collected breast cancer tissue samples from eight patients between January 2019 and June 2023 in our Hospital to analyse CIAPIN1 expression. We transfected human breast cancer cell lines (MCF7, MDA-MB-231, MDA-MB-453, and MDA-MB-468) with siRNA of CIAPIN1. Finally, we determined protein expression using RT-qPCR and Western blotting. CIAPIN1 expression was elevated in both breast cancer tissue and serum. Overexpression of CIAPIN1 detected in the breast cancer cell lines MCF7 and MDA-MB-468. In addition, CIAPIN1 overexpression increased cell proliferation and migration rate. CIAPIN1 downregulation suppressed cell proliferation while elevated cellular apoptosis, reactive oxygen species (ROS) production and oxidative stress in breast cancer cells. Moreover, CIAPIN1 inhibition remarkably suppressed pyruvate, lactate and adenosine triphosphate (ATP) production and reduced the pyruvate kinase M2 (PKM2) protein expression and phosphorylation of signal transducer and activator of transcription 3 (STAT3) in breast cancer cells. Downregulation of CIAPIN1 suppresses cell proliferation, migration and glycolysis capacity in breast cancer cells by inhibiting the STAT3/PKM2 pathway., (© 2024. The Author(s).)

Abnormal expression of circRNAs has been observed in different types of carcinomas, and they play significant roles in the biology of these cancers. Nevertheless, the clinical relevance and functional mechanisms of the majority of circRNAs implicated in breast cancer progression remain unclear. The primary objective of our investigation is to uncover new circRNAs in breast cancer and elucidate the underlying mechanisms by which they exert their effects. The circRNA expression profile data for breast cancer and RNA-sequencing data were acquired from distinct public databases. Differentially expressed circRNAs and mRNA were identified through fold change filtering. The establishment of the competing endogenous RNAs (ceRNAs) network relied on the interplay between circular RNAs, miRNAs, and mRNAs. The hub genes were identified from the protein-protein interaction (PPI) regulatory network using the CytoHubba plugin in Cytoscape. Moreover, the expression levels and prognostic value of these hub genes in the PPI network were assessed using the GEPIA and Kaplan-Meier plotter databases. Fluorescence in situ hybridization (FISH) was used to identified the expression and intracellular localization of hsa&#95;circ&#95;0059665 by using the tissue microarray. Transwell analysis and CCK-8 analysis were performed to assess the invasion, migration, and proliferation abilities of breast cancer cells. Additionally, we investigated the interactions between hsa&#95;circ&#95;0059665 and miR-602 through various methods, including FISH, RNA-binding protein immunoprecipitation (RIP), and luciferase reporter assay. Rescue experiments were conducted to determine the potential regulatory role of hsa&#95;circ&#95;0059665 in breast cancer progression. A total of 252 differentially expressed circRNAs were identified. Among them, 246 circRNAs were up-regulated, while 6 circRNAs were down-regulated. Based on prediction and screening of circRNA-miRNA and miRNA-mRNA binding sites, we constructed a network consisting of circRNA-miRNA-mRNA interactions. In addition, we constructed a Protein-Protein Interaction (PPI) network and identified six hub genes. Moreover, the expression levels of these six hub genes in breast cancer tissues were found to be significantly lower. Furthermore, the survival analysis results revealed a significant correlation between low expression levels of KIT, FGF2, NTRK2, CAV1, LEP and poorer prognosis in breast cancer patients. The FISH experiment results indicated that hsa&#95;circ&#95;0059665 exhibits significant downregulation in breast cancer, and its decreased expression is linked to poor prognosis in breast cancer patients. Functional in vitro experiments revealed that overexpression of hsa&#95;circ&#95;0059665 can inhibit proliferation, migration and invasion abilities of breast cancer cells. Further molecular mechanism studies showed that hsa&#95;circ&#95;0059665 exerts its anticancer gene role by acting as a molecular sponge for miR-602. In our study, we constructed and analyzed a circRNA-related ceRNA regulatory network and found that hsa&#95;circ&#95;0059665 can act as a sponge for miR-602 and inhibit the proliferation, invasion and migration of breast cancer cells., (© 2024. The Author(s).)

Breast cancer (BC) stands as a predominant global malignancy, significantly contributing to female mortality. Recently uncovered, histone lysine lactylation (kla) has assumed a crucial role in cancer progression. However, the correlation with lncRNAs remains ambiguous. Scrutinizing lncRNAs associated with Kla not only improves clinical breast cancer management but also establishes a groundwork for antitumor drug development. We procured breast tissue samples, encompassing both normal and cancerous specimens, from The Cancer Genome Atlas (TCGA) database. Utilizing Cox regression and XGBoost methods, we developed a prognostic model using identified kla-related lncRNAs. The model's predictive efficacy underwent validation across training, testing, and the overall cohort. Functional analysis concerning kla-related lncRNAs ensued. We identified and screened 8 kla-related lncRNAs to formulate the risk model. Pathway analysis disclosed the connection between immune-related pathways and the risk model of kla-related lncRNAs. Significantly, the risk scores exhibited a correlation with both immune cell infiltration and immune function, indicating a clear association. Noteworthy is the observation that patients with elevated risk scores demonstrated an increased tumor mutation burden (TMB) and decreased tumor immune dysfunction and exclusion (TIDE) scores, suggesting heightened responses to immune checkpoint blockade. Our study uncovers a potential link between Kla-related lncRNAs and BC, providing innovative therapeutic guidelines for BC management., (© 2024. The Author(s).)

Metal oxide nanoparticles(NPs) contain unique properties which have made them attractive agents in cancer treatment. The CuO nanoparticles were green synthesized using walnut shell powder in different calcination temperatures (400°, 500°, 700°, and 900 °C). The CuO nanoparticles are characterized by FTIR, XRD, BET, SEM and DLS analyses. SEM and DLS analyses showed that by increasing the required calcination temperature for synthesizing the NPs, their size was increased. DPPH analysis displayed no significant anti-oxidative properties of the CuO NPs. The MTT analysis showed that all synthesized CuO NPs exhibited cytotoxic effects on MCF-7, HCT-116, and HEK-293 cell lines. Among the CuO NPs, the CuO-900 NPs showed the least cytotoxic effect on the HEK-293 cell line (IC 50  = 330.8 µg/ml). Hoechst staining and real-time analysis suggested that the CuO-900 NPs induced apoptosis by elevation of p53 and Bax genes expression levels. Also, the CuO-900 NPs increased the Nrf-2 gene expression level in MCF-7 cells, despite the HCT-116 cells. As can be concluded from the results, the CuO-900 NPs exerted promising cytotoxic effects on breast and colon cancer cells., (© 2024. The Author(s).)

Carcinomas are associated with metastasis to specific organs while sparing others. Breast cancer presents with lung metastasis but rarely kidney metastasis. Using this difference as an example, we queried the mechanism(s) behind the proclivity for organ-specific metastasis. We used spontaneous and implant models of metastatic mammary carcinoma coupled with inflammatory tissue fibrosis, single-cell sequencing analyses and functional studies to unravel the causal determinants of organ-specific metastasis. Here we show that lung metastasis is facilitated by angiopoietin 2 (Ang2)-mediated suppression of lung-specific endothelial tight junction protein Claudin 5, which is augmented by the inflammatory fibrotic microenvironment and prevented by anti-Ang2 blocking antibodies, while kidney metastasis is prevented by non-Ang2-responsive Claudins 2 and 10. Suppression of Claudins 2 and 10 was sufficient to induce the emergence of kidney metastasis. This study illustrates the influence of organ-specific vascular heterogeneity in determining organotropic metastasis, independent of cancer cell-intrinsic mechanisms., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Metastasis is responsible for the majority of cancer-related fatalities. We previously identified specific cancer cell populations responsible for metastatic events which are cytokeratin-14 (CK14) and E-cadherin positive in luminal tumors, and E-cadherin and vimentin positive in triple-negative tumors. Since cancer cells evolve within a complex ecosystem comprised of immune cells and stromal cells, we sought to decipher the spatial interactions of these aggressive cancer cell populations within the tumor microenvironment (TME). We used imaging mass cytometry to detect 36 proteins in tumor microarrays containing paired primary and metastatic lesions from luminal or triple-negative breast cancers (TNBC), resulting in a dataset of 1,477,337 annotated cells. Focusing on metastasis-initiating cell populations, we observed close proximity to specific fibroblast and macrophage subtypes, a relationship maintained between primary and metastatic tumors. Notably, high CK14 in luminal cancer cells and high vimentin in TNBC cells correlated with close proximity to specific macrophage subtypes (CD163 int CD206 int PDL1 int HLA-DR + or PDL1 high ARG1 high ). Our in-depth spatial analysis demonstrates that metastasis-initiating cancer cells consistently colocalizes with distinct cell populations within the TME, suggesting a role for these cell-cell interactions in promoting metastasis., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Interest in the use of proteolysis-targeting chimeras (PROTACs) in cancer therapy has increased in recent years. Targeting bromodomain and extra terminal domain (BET) proteins, especially bromodomain-containing protein 4 (BRD4), has shown inhibitory effects on basal-like breast cancer (BLBC). However, the bioavailability of BRD4 PROTACs is restricted by their non-selective biodegradability and low tumor-targeting ability. We demonstrated that 6b (BRD4 PROTAC) suppresses BLBC cell growth by targeting BRD4, but not BRD2 and BRD3, for cereblon (CRBN)-mediated ubiquitination and proteasomal degradation. Compound 6b also inhibited expression of Krüppel-like factor 5 (KLF5) transcription factor, a key oncoprotein in BLBC, controlled by BRD4-mediated super-enhancers. Moreover, 6b inhibited HCC1806 tumor growth in a xenograft mouse model. The combination of 6b and KLF5 inhibitors showed additive effects on BLBC. These results suggest that BRD4-specific PROTAC can effectively inhibit BLBC by downregulating KLF5, and that 6b has potential as a novel therapeutic drug for BLBC., (© 2024. The Author(s).)

Tumour innervation is associated with worse patient outcomes in multiple cancers 1,2 , which suggests that it may regulate metastasis. Here we observed that highly metastatic mouse mammary tumours acquired more innervation than did less-metastatic tumours. This enhanced innervation was driven by expression of the axon-guidance molecule SLIT2 in tumour vasculature. Breast cancer cells induced spontaneous calcium activity in sensory neurons and elicited release of the neuropeptide substance P (SP). Using three-dimensional co-cultures and in vivo models, we found that neuronal SP promoted breast tumour growth, invasion and metastasis. Moreover, patient tumours with elevated SP exhibited enhanced lymph node metastatic spread. SP acted on tumoral tachykinin receptors (TACR1) to drive death of a small population of TACR1 high cancer cells. Single-stranded RNAs (ssRNAs) released from dying cells acted on neighbouring tumoural Toll-like receptor 7 (TLR7) to non-canonically activate a prometastatic gene expression program. This SP- and ssRNA-induced Tlr7 gene expression signature was associated with reduced breast cancer survival outcomes. Therapeutic targeting of this neuro-cancer axis with the TACR1 antagonist aprepitant, an approved anti-nausea drug, suppressed breast cancer growth and metastasis in multiple models. Our findings reveal that tumour-induced hyperactivation of sensory neurons regulates multiple aspects of metastatic progression in breast cancer through a therapeutically targetable neuropeptide/extracellular ssRNA sensing axis., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Dysregulated cellular proliferation represents a hallmark feature across all cancers. Aberrant activation of the cyclin-dependent kinase 4 and 6 (CDK4/6) pathway, independent of mitogenic signaling, engenders uncontrolled breast cancer cell proliferation. Consequently, the advent of CDK4/6 inhibition has constituted a pivotal milestone in the realm of targeted breast cancer therapy. The combination of CDK4/6 inhibitors (CDK4/6i) with endocrine therapy (ET) has emerged as the foremost therapeutic modality for patients afflicted with hormone receptor-positive (HR + )/HER2-negative (HER2-) advanced breast cancer. At present, the Food and Drug Administration (FDA) has sanctioned various CDK4/6i for employment as the primary treatment regimen in HR + /HER2- breast cancer. This therapeutic approach has demonstrated a substantial extension of progression-free survival (PFS), often amounting to several months, when administered alongside endocrine therapy. Within this comprehensive review, we systematically evaluate the utilization strategies of CDK4/6i across various subpopulations of breast cancer and explore potential therapeutic avenues following disease progression during application of CDK4/6i therapy., (© 2024. The Author(s).)

Translational control plays a crucial role in the regulation of apoptosis, with the EIF4 family serving as one of the mRNA translation factors that modulate the process of mRNA translation based on mRNA characteristics. To address this potential causal role of EIF4 family proteins and breast cancer, Mendelian randomization was employed. The study incorporated four sets of genetics instrumental variables, namely EIF4E, EIF4B, EIF4A, and EIF4EBP2. The outcome variables selected for analysis were the BCAC consortium, which included estrogen receptor positive (ER+) and estrogen receptor negative (ER-) samples. To assess the potential violations of the MR assumption, the primary MR analysis employed inverse variance weighted (IVW), and several sensitivity analyses were conducted. The findings of the two-sample MR analysis indicate that EIF4E has an adverse effect on breast cancer risk (p = 0.028). However, the evidence for the relationship between EIF4E and ER status of breast cancer suggests a weak association with ER+ breast cancer (p = 0.054), but not with ER- breast cancer (p > 0.05). The study findings indicate that EIF4A is not causally linked to the risk of ER+ breast cancer, but is significantly associated with an elevated risk of ER- breast cancer (p = 0.028). However, the evidence is inadequate to support the effects of EIF4B and EIF4EBP2 on breast cancer (p > 0.05). Our results suggest that EIF4 may be a potential factor in the occurrence and development of breast cancer, which may lead to a better understanding of its causes and prevention., (© 2024. The Author(s).)

During metastasis, cancer cells traverse the vasculature by squeezing through very small gaps in the endothelium. Thus, nuclei in metastatic cancer cells must become more malleable to move through these gaps. Our lab showed invasive breast cancer cells have 50% less emerin protein resulting in smaller, misshapen nuclei, and higher metastasis rates than non-cancerous controls. Thus, emerin deficiency was predicted to cause increased nuclear compliance, cell migration, and metastasis. We tested this hypothesis by downregulating emerin in noninvasive MCF7 cells and found emerin knockdown causes smaller, dysmorphic nuclei, resulting in increased impeded cell migration. Emerin reduction in invasive breast cancer cells showed similar results. Supporting the clinical relevance of emerin reduction in cancer progression, our analysis of 192 breast cancer patient samples showed emerin expression inversely correlates with cancer invasiveness. We conclude emerin loss is an important driver of invasive transformation and has utility as a biomarker for tumor progression., (© 2024. The Author(s).)

Globally, the prevalence of breast cancer (BC) is increasing at an alarming level, despite early detection and technological improvements. Alkaloids are diverse chemical groups, and many within this class have been reported as potential anticancer compounds. Chabamide F (F) and chabamide G (G) are two dimeric amide alkaloids found in a traditional medicinal plant, Piper chaba, and possess significant cytotoxic effects. However, their scientific rationalization in BC remains unknown. Here, we aimed to investigate their potential and molecular mechanisms for BC through in silico approaches. From network pharmacology, we identified 64 BC-related genes as targets. GO and KEGG studies showed that they were involved in various biological processes and mostly expressed in BC-related pathways such as RAS, PI3K-AKT, estrogen, MAPK, and FoxO pathways. However, PPI analysis revealed SRC and AKT1 as hub genes, which play key roles in BC tumorigenesis and metastasis. Molecular docking revealed the strong binding affinity of F (- 10.7 kcal/mol) and G (- 9.4 and - 11.7 kcal/mol) for SRC and AKT1, respectively, as well as the acquisition of vital residues to inhibit them. Their long-term stability was evaluated using 200 ns molecular dynamics simulation. The RMSD, RMSF, Rg, and SASA analyses showed that the G-SRC and G-AKT1 complexes were excellently stable compared to the control, dasatinib, and capivasertib, respectively. Additionally, the PCA and DCCM analyses revealed a significant reduction in the residual correlation and motions. By contrast, the stability of the F-SRC complex was greater than that of the control, whereas it was moderately stable in complex with AKT1. The MMPBSA analysis demonstrated higher binding energies for both compounds than the controls. In particular, the binding energy of G for SRC and AKT1 was - 120.671 ± 16.997 and - 130.437 ± 19.111 kJ/mol, respectively, which was approximately twice as high as the control molecules. Van der Waal and polar solvation energies significantly contributed to this energy. Furthermore, both of them exhibited significant interactions with the binding site residues of both proteins. In summary, this study indicates that these two molecules could be a potential ATP-competitive inhibitor of SRC and an allosteric inhibitor of AKT1., (© 2024. The Author(s).)

Breast cancer is a prevalent malignancy affecting women globally, necessitating effective treatment strategies. This study explores the potential of ergosterol, a bioactive compound found in edible mushrooms, as a candidate for breast cancer treatment. Breast cancer cell lines (MCF-7 and MDA-MB-231) were treated with ergosterol, revealing its ability to inhibit cell viability, induce cell cycle arrest, and suppress spheroid formation. Mechanistically, ergosterol demonstrated significant inhibitory effects on the Wnt/beta-catenin signaling pathway, a critical regulator of cancer progression, by attenuating beta-catenin translocation in the nucleus. This suppression was attributed to the inhibition of AKT/GSK-3beta phosphorylation, leading to decreased beta-catenin stability and activity. Additionally, ergosterol treatment impacted protein synthesis and ubiquitination, potentially contributing to its anti-cancer effects. Moreover, the study revealed alterations in metabolic pathways upon ergosterol treatment, indicating its influence on metabolic processes critical for cancer development. This research sheds light on the multifaceted mechanisms through which ergosterol exerts anti-tumor effects, mainly focusing on Wnt/beta-catenin pathway modulation and metabolic pathway disruption. These findings provide valuable insights into the potential of ergosterol as a therapeutic candidate for breast cancer treatment, warranting further investigation and clinical application., (© 2024. The Author(s).)

The most devastating feature of cancer cells is their ability to metastasize to distant sites in the body. HER2 + and TN breast cancers frequently metastasize to the brain and stay potentially dormant for years until favorable conditions support their proliferation. The sheltered and delicate nature of the brain prevents, however, early disease detection and effective delivery of therapeutic drugs. Moreover, the challenges associated with the acquisition of brain biopsies add compounding difficulties to exploring the mechanistic aspects of tumor development. To provide insights into the determinants of cancer cell behavior at the brain metastatic site, this study was aimed at exploring the early response of HER2 + breast cancer cells (SKBR3) to factors present in the brain perivascular niche. The neural microenvironment was simulated by using the secretome of a set of brain cells that come first in contact with the cancer cells upon crossing the blood brain barrier, i.e., endothelial cells, astrocytes, and microglia. Cytokine microarrays were used to investigate the secretome mediators of intercellular communication, and proteomic technologies for assessing the changes in the behavior of cancer cells upon exposure to the brain cell-secreted factors. The cytokines detected in the brain secretomes were supportive of inflammatory conditions, while the SKBR3 cells secreted numerous cancer-promoting growth factors that were either absent or present in lower abundance in the brain cell cultures, indicating that upon exposure the SKBR3 cells may have been deprived of favorable conditions for optimal growth. Altogether, the results suggest that the exposure of SKBR3 cells to the brain cell-secreted factors altered their growth potential and drove them toward a state of quiescence, with broader overall outcomes that affected cellular metabolism, adhesion and immune response processes. The findings of this study underscore the key role played by the neural niche in shaping the behavior of metastasized cancer cells, provide insights into the cellular cross-talk that may lead cancer cells into dormancy, and highlight novel opportunities for the development of metastatic breast cancer therapeutic strategies., (© 2024. The Author(s).)

The FRG1(FSHD region gene 1) gene has emerged as a pivotal tumor suppressor in both breast and prostate cancer. HPF1 (Histone PARylation Factor 1), a gene crucial in the base excision repair (BER) mechanism for single-stranded DNA (ssDNA) lesions, showcases a robust correlation with FRG1. This implies that FRG1 might have the capacity to influence BER via HPF1, potentially playing a role in tumorigenesis. Using a comprehensive approach that integrates in-silico analyses involving differential gene expression, KEGG (Kyoto Encyclopedia of Genes and Genomes), GO (Gene Ontology), and STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) databases, we unravelled the intricate network of genes and pathways influenced by FRG1, which includes BER. Our linear regression analysis unveiled a positive relationship between FRG1 and key genes crucial for BER. Notably, breast cancer patients with low FRG1 expression exhibited a significantly higher frequency of mutation in TP53. To enhance the accuracy of our analysis, we conducted qRT-PCR assays, which demonstrated that FRG1 affects the transcription of DNA base excision repair genes, showing differential expression in breast cancer cells. Moreover, through the Alkaline Comet Assay, a technique that quantifies DNA damage at the single-cell level, we observed diminished DNA repair capabilities when FRG1 levels are low. Risk scores were calculated using the Cox regression coefficients, and we found notable differences in Overall Survival (OS) and mRNA expression of DEGs in the low and high-risk groups. In summary, our findings shed light on the pivotal role of FRG1 in maintaining DNA repair efficiency within breast cancer cells., (© 2024. The Author(s).)

To compare the magnetic resonance imaging (MRI) features of different immunophenotypes of breast carcinoma of no special type (NST), with special attention to estrogen receptor (ER)-low-positive breast cancer. This retrospective, single-centre, Institutional Review Board (IRB)-approved study included 398 patients with invasive breast carcinoma. Breast carcinomas were classified as ER-low-positive when there was ER staining in 1-10% of tumour cells. Pretreatment MRI was reviewed to assess the tumour imaging features according to the 5th edition of the Breast Imaging Reporting and Data System (BI-RADS) lexicon. Of the 398 cases, 50 (12.6%) were luminal A, 191 (48.0%) were luminal B, 26 (6.5%) were luminal ER-low positive, 64 (16.1%) were HER2-overexpressing, and 67 (16.8%) were triple negative. Correlation analysis between MRI features and tumour immunophenotype showed statistically significant differences in mass shape, margins, internal enhancement and the delayed phase of the kinetic curve. An oval or round shape and rim enhancement were most frequently observed in triple-negative and luminal ER-low-positive tumours. Spiculated margins were most common in luminal A and luminal B tumours. A persistent kinetic curve was more frequent in luminal A tumours, while a washout curve was more common in the triple-negative, HER2-overexpressing and luminal ER-low-positive immunophenotypes. Multinomial regression analysis showed that luminal ER-low-positive tumours had similar results to triple-negative tumours for almost all variables. Luminal ER-low-positive tumours present with similar MRI findings to triple-negative tumours, which suggests that MRI can play a fundamental role in adequate radiopathological correlation and therapeutic planning in these patients., (© 2024. The Author(s).)