MAL/SPP1 axis drives tumor proliferation and immune evasion via JAK2/STAT3 and MHC class Ib in breast cancer.

Hecogenin derivative as an anti-breast cancer agent: Mechanistic insights from multi-computational analysis.

Breast cancer remains a leading cause of morbidity and mortality among women worldwide, necessitating in-depth research into its molecular mechanisms to improve prognosis and treatment strategies. This study investigates the expression profile and functional role of heparan sulfate proteoglycan Syndecan-1 (SDC1) in breast cancer progression, with a focus on its downstream signaling pathways. Utilizing bioinformatics analysis of datasets from the GEO and TCGA databases, we identified significantly elevated SDC1 expression in breast cancer tissues compared to normal counterparts, correlating with advanced tumor stage, lymph node metastasis, and poor survival outcomes. Clinical sample validation through RT-qPCR and Western blot confirmed SDC1 overexpression in breast cancer tissues and cell lines. Functional experiments, including SDC1 knockdown via lentiviral infection, revealed that reduced SDC1 expression markedly impairs breast cancer cell proliferation, migration, and angiogenesis, as evidenced by CCK-8, EdU, wound healing, Transwell, and tube formation assays. Mechanistically, transcriptome sequencing and Western blot analysis demonstrated that SDC1 knockdown significantly suppressed the phosphorylation of key MAPK pathway components (ERK1/2, JNK, and p38). Rescue experiments using the MAPK agonist C16-PAF effectively reversed the inhibitory effects of SDC1 knockdown on cell proliferation, migration, and angiogenesis. Furthermore, invivo xenograft models confirmed that SDC1 knockdown suppressed tumor growth and reduced microvessel density, while C16-PAF treatment partially reversed these effects. Collectively, our findings demonstrate that SDC1 promotes breast cancer progression by activating the MAPK signaling pathway, highlighting SDC1 as a potential prognostic biomarker and therapeutic target in breast cancer.

Metformin Induces Ferroptosis and Inhibits Malignant Progression in Diabetic Breast Cancer.

Emerging evidence indicates that tumour innervation promotes cancer progression via a non-canonical TLR7 signalling pathway. However, its impact across breast cancer subtypes, patient populations, associated molecular pathways, and oncogenic drivers remains poorly defined. We analysed TLR7 signature scores in human breast cancer across multiple datasets and evaluated their associations with prognosis, clinical outcomes, TNBC subtypes, metastasis, molecular signatures, oncogenic signalling, and pathological complete response. We demonstrate that the TLR7score signature is significantly elevated in triple-negative breast cancer (TNBC) - the most aggressive breast cancer subtype-compared with ER⁺ disease. Within TNBC, high TLR7 signalling characterises basal- and mesenchymal-like tumours relative to the luminal androgen receptor (LAR) subtype. Across multiple breast cancer cohorts, including TNBC, TLR7score alone does not uniformly predict prognosis, as both high- and low-scoring tumours are associated with reduced survival. Using sequential cut-off analysis in seven independent clinical cohorts, we show that both TLR7score-high (e.g. HR = 4.7, P = 0.01) and TLR7score-low (HR = 3.37, P = 0.038) tumours are associated with unfavourable outcomes relative to intermediate-score tumours. TLR7score-high lesions are enriched for cell proliferation, neuronal, and mast cell-related pathways, as well as RB1 and TP53 loss and elevated E2F, PI3K, MET, and MYC signalling. In contrast, TLR7score-low tumours show increased ER signalling and are enriched for T cell-associated but not neuronal pathways, delineating innervated versus non-innervated TNBC phenotypes. Moreover, TLR7score correlates with pathological complete response (pCR) in a treatment-dependent manner. Collectively, these findings suggest that TNBC progression involves both TLR7-dependent and TLR7-independent mechanisms and that TLR7score may enable patient stratification for distinct therapeutic strategies.

"Targeting platelets in breast cancer: Insights into pathophysiology and therapeutic strategies".

Breast cancer (BC) is the most frequent cancer among women globally. CD14high expression levels are associated with more aggressive behavior. The study aims to assess CD14 expressions in locally recurrent breast cancer and corresponding primary tumors whenever available, both intratumorally and peritumorally, and to analyze its association with clinicopathological features. This retrospective cross-sectional study included 55 cases of women with locally recurrent breast cancer. They were immunohistochemically stained using anti-CD14 antibody. Statistical associations between CD14 expression and available clinicopathological data were done. Immunoexpression of CD14 was positive peritumorally in (50.9%) of the recurrent breast cancer cases. In the 18 available corresponding primary breast cancer, CD14 was positive only in 2 cases (11.1%) peritumorally. There was significant association between CD14-positive peritumoral immunohistochemical expression with molecular subtype (luminal B), Ki67 (≥14) and the early recurrence time (≤5 years), P values were (0.002, <0.001 & 0.042) respectively. Peritumoral CD14 positivity was significantly higher in recurrent breast cancer cases (50.9%) than in available primary ones (11.1%). CD14 positivity was higher in recurrent than in primary breast cancer, and its statistically significant association with early recurrence and high Ki67 suggests a potential role in breast cancer progression.

Breast cancer remains a major threat to women's health worldwide, and exploring novel therapeutic targets is urgently needed. Inhibiting 5-lipoxygenase (5-LOX) showed promising potential in treating various malignancies. However, 5-LOX effects on breast cancer progression are largely unknown. Breast cancer cell lines (MCF-7 and MDA-MB-231) and nonmalignant breast epithelial cells (MCF-10A) were used in this study. The expression of 5-LOX was quantified by RT-qPCR and Western blot analysis. 5-LOX was upregulated by pCDNA3.1(+)-5-LOX transfection and inhibited using zileuton. The influence of 5-LOX modulation on cell apoptosis, invasion, and colony formation was determined using flow cytometry, Transwell invasion assay, and colony formation assay, respectively. Results demonstrated that 5-LOX mRNA and protein expression levels were significantly higher in breast cancer cells compared with nonmalignant breast epithelial cells. Transfection with pCDNA3.1(+)-5-LOX significantly upregulated 5-LOX expression, while zileuton, an anti-inflammatory leukotriene inhibitor of 5-LOX, treatment (400 μmol/L) markedly downregulated 5-LOX mRNA and protein levels. Treatment with zileuton significantly induced apoptosis in MCF-7 and inhibited in MDA-MB-231 cell invasion. Further, zileuton suppressed colony formation in both breast cancer cell lines. Data suggest that 5-LOX may serve as a potential therapeutic target for breast cancer, and zileuton warrants further investigation as a candidate anti-cancer agent.

The YAP-TEAD4 inhibitor M511-0965 suppresses triple-negative breast cancer progression by downregulating TGFB2.

A high-cholesterol diet is a risk factor for breast cancer (BC) progression. Clofibrate, a PPARα agonist, is implicated in lipid metabolism and tumor prevention, yet its precise mechanism in BC remains unclear. To investigate the mechanism of action of Clofibrate, we utilized the Therapeutic Target Database. We constructed models of MELK silencing and overexpression, and assessed the effects of Clofibrate, MELK silencing, and MELK overexpression on BC using clone formation assays, wound healing assays, apoptosis assays, and tumor-bearing mouse experiments. Western blot (WB) analysis was performed to detect the expression of HRD-related proteins (BRCA1, BRCA2, and RAD51) in BC cells after MELK silencing. Additionally, WB was used to examine the impact of Clofibrate on the expression of MELK protein and HRD-related proteins (BRCA1, BRCA2, and RAD51) in BC cells. Gene set enrichment analysis was conducted to explore the potential mechanism by which Clofibrate regulates HRD, with findings validated by WB. Clofibrate significantly inhibited proliferation, migration, and induced apoptosis in MDA-MB-231 cells. This anti-cancer effect was also observed in tumor-bearing mice. Mechanistically, Clofibrate treatment led to the downregulation of MELK and key HRD-related proteins (BRCA1, BRCA2, and RAD51). GSEA analysis and subsequent experimental validation further implicated the AKT-mTOR signaling axis as a potential downstream effector of MELK in this process. Taken together, our findings suggest that Clofibrate downregulates key DNA damage response proteins (BRCA1, BRCA2, and RAD51) in BC, an effect that is associated with suppression of the MELK-AKT-mTOR signaling pathway.

Breast cancer (BC) is one of the most common malignant tumors in women worldwide, with metastasis and recurrence constituting major therapeutic challenges. F-Box Protein 5(FBXO5), a core component of the E3 ubiquitin ligase complex, is overexpressed in multiple cancers, but its specific role and underlying mechanism in BC remain unclear and require further investigation. We screened E3 ubiquitin ligase-related cancer dependency genes by integrating data from the DepMap and UniProt databases, and further analyzed transcriptomic data from TCGA and GEO to identify the candidate gene FBXO5. We then validated its expression at the mRNA and protein levels in BC tissues from two independent centers and in cell lines, employing qRT-PCR, Western blot, and immunohistochemistry.The effects of FBXO5 on the proliferation, migration, and invasion abilities of BC cells were evaluated in vitro and in vivo through colony formation, CCK8, Transwell assays, wound healing assays, IHC, and subcutaneous tumor formation in nude mice. The interactions between FBXO5 and proteins, as well as its main functions and pathways, were investigated using Co-IP, mass spectrometry, immunofluorescence confocal microscopy, molecular docking and bioinformatics analysis, with results validated by rescue experiments. The mRNA and protein expression levels of FBXO5 were significantly upregulated in BC tissues from two centers, high expression of FBXO5 was significantly correlated with adverse clinicopathological features, including larger tumor size, positive nodal status, and elevated Ki-67, and was associated with poor overall survival (OS) and disease-free survival (DFS).In vitro and in vivo experiments confirmed that FBXO5 significantly affected the proliferation, invasion, and migration abilities of BC cells. Mechanistically, Co-IP, mass spectrometry, molecular docking and immunofluorescence confocal microscopy experiments confirmed that FBXO5 directly interacts with ribosomal protein L23a (RPL23A) and promotes its polyubiquitination at the K48 chain, thereby regulating its degradation. Further experiments showed that the ubiquitination-mediated degradation of RPL23A led to a decrease in the stability of Tumor Protein p53(p53) and facilitated its degradation by Proto-Oncogene MDM2 (MDM2). Our study establishes the existence of a novel FBXO5/RPL23A/MDM2/p53 oncogenic axis in BC. These findings thereby nominate FBXO5 as a promising therapeutic target for BC intervention.

AF9-KLF2 gene regulatory circuit links histone lactylation to metabolic reprogramming and breast cancer progression.

Myeloid-derived suppressor cells (MDSCs) are essential immunosuppressive elements found within the tumor microenvironment (TME) and significantly influence the development of breast cancer (BC). Given their critical role in cancer progression, identifying MDSC-related genes is urgently needed to develop more effective treatment strategies for BC patients. The integration of bulk RNA-seq data from the TCGA-BC cohort alongside scRNA-seq data from the GSE176078 dataset was performed for identifying MDSC-related genes through bioinformatic analysis. Subsequently, the potential of the hub gene BASP1 in predicting prognosis and immune infiltration in BC was evaluated. Furthermore, the functional role of BASP1 in BC was investigated both in vitro and in vivo. Notably, BASP1 levels were significantly higher in BC tissues than in adjacent normal tissues, and elevated BASP1 expression was closely associated with adverse clinical outcomes. Additionally, BC patients with increased BASP1 levels exhibited increased infiltration of immunosuppressive cells (M2 macrophages and Tregs) but reduced infiltration of CD8 + T cells. Functionally, downregulation of BASP1 was observed to suppress BC cell proliferation and migration in vitro through inactivation of AKT and ERK signalings. Mechanistically, BASP1 in 4T1 cells promoted MDSC migration, at least partially, via upregulating CXCL12 secretion, while BASP1 in MDSCs directly suppressed T cell function. In vivo experiments showed that BASP1 knockdown markedly inhibited tumor growth in mouse models bearing 4T1 tumors, accompanied by decreased MDSCs infiltration and increased Granzyme B + CD8 + T cell accumulation in tumor tissues. Collectively, BASP1 may serve as a potential prognostic biomarker and a therapeutic target for BC intervention, functioning both as a pro-tumorigenic gene and as an immunomodulatory molecule that shapes an immunosuppressive microenvironment.

Breast cancer (BC) is the most prevalent cancer in women globally, with axillary lymph node metastasis (LNM) and distant metastasis being key prognostic factors linked to survival. Circulating low-density neutrophils (LDNs) in cancer patients are associated with tumor-supportive role. This study assessed the clinical relevance of combining circulating LDNs with hematological indicators in BC patients with LNM. Peripheral blood samples from 184 BC patients were analyzed using flow cytometry to measure the LDNs levels. Lasso logistic regression was used for variable selection, and univariate and multivariate logistic regression identified independent risk factors. A predictive nomogram was developed and validated with an external cohort. LDNs were elevated in BC patients, especially those with LNM. Seven variables-LDNs, CEA, CA153, PLR, SIRI, NMLR, and NHR-were identified for further analysis. Multivariate logistic regression identified five of these as independent risk factors for LNM: LDNs (OR = 2.307, P = 0.032), CEA (OR = 4.027, P < 0.001), CA153 (OR = 2.440, P = 0.016), PLR (OR = 2.563, P = 0.014), and SIRI (OR = 4.617, P = 0.003). The nomogram model based on these factors demonstrated good predictive performance with an optimism-corrected C-statistic of 0.780, consistent in the external validation set (AUC = 0.762). The calibration curve confirmed good clinical applicability. This study suggests circulating LDNs levels may be potential biomarkers for BC progression, and a nomogram combing LDNs with other hematological indicators shows potential for identifying patients with LNM.

Breast cancer (BC) progression is strongly influenced by the tumor microenvironment (TME), where dynamic interactions between cancer cells, stromal components, and secreted factors drive tumor heterogeneity and aggressiveness. Among these factors, endothelial cell-specific molecule 1 (ESM1), a soluble dermatan sulfate proteoglycan, has emerged as a key regulator of tumor–microenvironment crosstalk. ESM1 promotes angiogenesis, inflammation, and cancer cell proliferation and migration, and is frequently overexpressed in multiple malignancies. However, its role in modulating the TME in breast cancer remains poorly defined. In this study, we evaluated serum and tissues ESM1 levels in BC patients and found that HER2-negative cases exhibit higher and more heterogeneous ESM1 levels. Based on these findings, we investigated the functional role of ESM1 silencing in the triple-negative breast cancer (TNBC) cell line MDA-MB-231. ESM1 silencing led to significant modulation of pathways involved in extracellular matrix remodeling and epithelial-to-mesenchymal transition (EMT). Collectively, our findings indicate that ESM1 acts as a critical mediator of tumor–TME interactions, contributing to the aggressive phenotype of TNBC, and identify ESM1 as a promising biomarker and potential therapeutic target in breast cancer, supporting its possible integration into precision medicine strategies for patient stratification and targeted intervention.Acknowledgments: This research was supported by the Italian Ministry of Education, University, and Research (MIUR) through the PRIN PNRR 2022 project P2022WZXRP_002 (PRJ-1560) and the INTERREG NEXT Italia Tunisia project BIOGEN4MED - Discovering novel Biomarkers through Pharmaco-Genomics for Precision Medicine - B73C25000310002

Breast cancer stem cells are recognized as the key factors contributing to breast cancer progression and drug resistance, while polarity proteins play a pivotal role in regulating the fate of cancer stem cells and the progression of malignant tumors. However, the function of the polarity protein MALS3 in modulating cancer stem cell-like properties remains unclear. Here, we identify that the loss of the polarity protein MALS3 disrupts the homeostasis of mammary epithelial cells while increasing breast cancer stem cell-like properties. Mechanistically, MALS3 utilizes its L27 domain to mediate the interaction between the kinase LATS1 and TAZ, thereby promoting the phosphorylation of TAZ. Furthermore, MALS3 can recruit the E3 ubiquitin ligase TRIM29 to interact with TAZ. Subsequently, TRIM29 ultimately drives the degradation of TAZ via K48-linked polyubiquitination, and this regulatory process operates independently of the classical Hippo signaling pathway. We discover that the MALS3 upregulator mirtazapine suppresses stem cell-like properties and effectively enhances tumor sensitivity to doxorubicin in vivo. This study reveals the molecular mechanism by which the polarity protein MALS3 regulates breast cancer stem cell-like properties and suggests that MALS3 upregulation via mirtazapine may enhance tumor sensitivity to chemotherapeutic drugs.

Construction of psoralen - loaded targeted polymeric nanoparticles for enhanced anti - triple negative breast cancer efficacy via modulation of tumor associated macrophages in vitro.

G protein-coupled receptor 17 (GPR17), a Gi protein-coupled receptor, has been defined poorly about its roles and clinical significance in triple-negative breast cancer (TNBC). The biological expression profile, prognostic value and functional roles of GPR17 in TNBC were elucidated in the present study. Differentially expressed genes were screened through comprehensive bioinformatics analyses of the GSE233242 dataset. GPR17 expression patterns and their prognostic significance in TNBC were evaluated based on the UALCAN, bc-GenExMiner v4.8 and KM-Plotter databases. Prognostic correlations of GPR17 were further validated in a retrospective cohort comprising 163 TNBC patients. In vitro functional assays for cell proliferation, migration and invasion were conducted in MDA-MB-231 and MDA-MB-453 cells after GPR17 overexpression. GPR17 was significantly downregulated in TNBC tumor tissues (p < 0.001), and reduced GPR17 expression was associated with more aggressive tumor phenotypes in TNBC patients. GPR17 expression was closely correlated with clinical T stage and lymph node metastasis, and was identified as an independent prognostic factor for the disease. Ectopic GPR17 overexpression significantly suppressed the proliferative, migratory and invasive capacities of MDA-MB-231 and MDA-MB-453 TNBC cell lines. GPR17 holds potential as a novel prognostic biomarker for TNBC, with its expression levels closely associated with tumor progression and able to predict clinical outcomes in TNBC patients.

Background Vitamin D is a steroid hormone with many vital physiological functions. There is extensive research suggesting that vitamin D additionally acts as a protective factor against the development and progression of breast cancer. However, there is limited detail regarding the effect of vitamin D insufficiency or deficiency on the clinicopathologic characteristics of breast cancer. Methods A retrospective analysis of all the breast cancer patients that had received treatment at the Algoma District Cancer Program, Ontario, Canada between 2016 and 2024 was conducted. Patients were grouped according to their circulating 25-hydroxyvitamin D levels as sufficient (25-hydroxyvitamin D- 25-OHD ≥ 75 nmol/L) or insufficient (25-OHD < 75 nmol/L). The groups were compared for demographic and tumor characteristics along with outcomes. An analysis according to 25-OHD deficiency (25-OHD < 50 nmol/L) was also performed. Results Patients with vitamin D sufficiency represented 55.7% (295 of 530 patients) of the whole cohort, while patients with vitamin D insufficiency represented 44.3% (235 of 530 patients) in the cohort. Patients with vitamin D sufficiency were older, less likely to be obese, and were more likely to have tumors with high estrogen receptor (ER) expression. Vitamin D insufficient patients had shorter overall survival (LogRank test p = .02). The association, however, was lost on the multivariate analysis. Conclusions Vitamin D sufficiency in breast cancer patients is associated with older age and lower obesity rates, along with favorable tumor prognostic indicators like high ER expression. Maintaining vitamin D sufficiency may improve breast cancer outcomes.

Extracellular heat shock protein 90 alpha (eHsp90α) has been implicated in promoting cancer cell invasion and metastasis. However, the role of eHsp90α in the tumor microenvironment remains poorly understood. In the present study, we provide the first evidence that eHsp90α aggravates the invasiveness of cancer-associated fibroblasts (CAFs) through low-density lipoprotein receptor-related protein 1 (LRP1) and consequent upregulation of epithelial-mesenchymal transition (EMT)-associated transcription factor expression. We observed that eHsp90α induces CAFs invasiveness. However, silencing of Twist, Snail and Slug expressions significantly attenuated eHsp90α-induced CAFs invasiveness. In addition, transfecting CAFs with LRP1 short interfering RNA (siRNA) markedly inhibited eHsp90α-induced CAFs invasion and EMT-associated transcription factor expression. Intriguingly, we observed that the epidermal growth factor receptor (EGFR)/AKT signaling is located downstream of LRP1 and governs eHsp90α-induced Twist and Snail but not Slug expression required for CAFs invasion. Moreover, we demonstrated that these EMT-associated transcription factors of CAFs are indispensable for breast cancer cell invasion. Collectively, the present data reveal that eHsp90α increases CAFs invasiveness through LRP1 and subsequent EMT-associated transcription factor expression to promote breast cancer invasion, presenting potential therapeutic targets to impede breast cancer progression.