Breast Cancer Microenvironment Research Articles

Prognostic and therapeutic implications of tumor-restrictive type III collagen in the breast cancer microenvironment

Collagen plays a critical role in regulating breast cancer progression and therapeutic resistance. An improved understanding of both the features and drivers of tumor-permissive and -restrictive collagen matrices are critical to improve prognostication and develop more effective therapeutic strategies. In this study, using a combination of in vitro, in vivo and bioinformatic experiments, we show that type III collagen (Col3) plays a tumor-restrictive role in human breast cancer. We demonstrate that Col3-deficient, human fibroblasts produce tumor-permissive collagen matrices that drive cell proliferation and suppress apoptosis in non-invasive and invasive breast cancer cell lines. In human triple-negative breast cancer biopsy samples, we demonstrate elevated deposition of Col3 relative to type I collagen (Col1) in non-invasive compared to invasive regions. Similarly, bioinformatics analysis of over 1000 breast cancer patient biopsies from The Cancer Genome Atlas BRCA cohort revealed that patients with higher Col3:Col1 bulk tumor expression had improved overall, disease-free, and progression-free survival relative to those with higher Col1:Col3 expression. Using an established 3D culture model, we show that Col3 increases spheroid formation and induces the formation of lumen-like structures that resemble non-neoplastic mammary acini. Finally, our in vivo study shows co-injection of murine breast cancer cells (4T1) with rhCol3-supplemented hydrogels limits tumor growth and decreases pulmonary metastatic burden compared to controls. Taken together, these data collectively support a tumor-suppressive role for Col3 in human breast cancer and suggest that strategies that increase Col3 may provide a safe and effective therapeutic modality to limit recurrence in breast cancer patients.

Non-metabolic enzyme function of pyruvate kinase M2 in breast cancer

Breast cancer (BC) is a prevalent malignant tumor in women, and its incidence has been steadily increasing in recent years. Compared with other types of cancer, it has the highest mortality and morbidity rates in women. So, it is crucial to investigate the underlying mechanisms of BC development and identify specific therapeutic targets. Pyruvate kinase M2 (PKM2), an important metabolic enzyme in glycolysis, has been found to be highly expressed in BC. It can also move to the nucleus and interact with various transcription factors and proteins, including hypoxia-inducible factor-1α (HIF-1α), signal transducer and activator of transcription 3 (STAT3), β-catenin, cellular-myelocytomatosis oncogene (c-Myc), nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), and mammalian sterile 20-like kinase 1 (MST1). This interaction leads to non-metabolic functions that control the cell cycle, proliferation, apoptosis, migration, invasion, angiogenesis, and tumor microenvironment in BC. This review provides an overview of the latest advancements in understanding the interactions between PKM2 and different transcription factors and proteins that influence the initiation and progression of BC. It also examined how natural drugs and noncoding RNAs affect various biological processes in BC cells through the regulation of the non-metabolic enzyme functions of PKM2. The findings provide valuable insights for improving the prognosis and developing targeted therapies for BC in the coming years.

Elevated expression of ELK1 promotes breast cancer cell growth and correlates with poor prognosis of breast cancer patients

Background: Breast cancer is the most common tumor in women and poses a serious threat to women’s physical and mental health. The ETS-like gene 1 (ELK1), upregulated in various malignancies, serves as a transcription regulatory factor. This study primarily investigates the biological functions and prognostic significance of ELK1 in breast cancer. Materials and methods: The authors conducted an analysis of ELK1 expression in breast cancer and adjacent tissues using data from The Cancer Genome Atlas (TCGA), and validated these findings with clinical specimens. Additionally, the authors employed siRNA transfection, proliferation and apoptosis assays to elucidate the roles of ELK1 in breast cancer cells. Furthermore, we assessed the correlations between ELK1 expression and the tumor microenvironment, as well as tumor-infiltrating immune cells (TIICs), utilizing the ESTIMATE and CIBERSORT algorithms. Finally, we used Kaplan–Meier plots and COX regressions to identify prognostic factors, and developed a predictive alignment diagram to evaluate the prognostic significance of ELK1 in breast cancer. Results: A marked increase in ELK1 expression is evident in breast cancer tissues (P<0.01). Experimental findings demonstrate that silencing ELK1 suppresses proliferation and promotes apoptosis in breast cancer cells. ELK1 plays a pivotal role in regulating the immune microenvironment of breast cancer. Furthermore, the alignment diagram indicates that ELK1 may serve as an independent prognostic factor for breast cancer patients. Conclusion: The authors’ study reveals that ELK1 exhibits a high expression level in breast cancer tissues and is associated with disease progression and poor prognosis.

HSP90 promotes tumor associated macrophage differentiation during triple-negative breast cancer progression.

Tumor-associated macrophages (TAMs) originating from monocytes are crucial for cancer progression; however, the mechanism of TAM differentiation is unclear. We investigated factors involved in the differentiation of monocytes into TAMs within the tumor microenvironment of triple-negative breast cancer (TNBC). We screened 172 compounds and found that a heat shock protein 90 (HSP90) inhibitor blocked TNBC-induced monocyte-to-TAM differentiation in human monocytes THP-1. TNBC-derived conditional medium (CM) activated cell signaling pathways, including MAP kinase, AKT and STAT3, and increased the expression of TAM-related genes and proteins. These inductions were suppressed by HSP90 inhibition or by knockdown of HSP90 in TNBC. Additionally, we confirmed that TNBC secreted HSP90 extracellularly and that HSP90 itself promoted TAM differentiation. In a mouse tumor model, treatment with an HSP90 inhibitor suppressed tumor growth and reduced TAMs in the tumor microenvironment. Our findings demonstrate the role of HSP90 in TAM differentiation, suggesting HSP90 as a potential target for TNBC immunotherapy due to its regulatory role in monocyte-to-TAM differentiation.

The Role of Breastmilk in Macrophage-Tumour Cell Interactions in Postpartum Breast Cancer

Background: Lactation is associated with long-term reduced risk of breast cancer. However, there is a transient increased risk of breast cancer in the 5 to 10 years postpartum and this is associated with a high incidence of metastasis and mortality. Breastmilk is a physiological fluid secreted by the mammary glands intimately connected with breast cells and the microenvironment that may affect postpartum breast cancer development and progression. This study aims to investigate the effect of breastmilk on interactions between breast cancer cells and macrophages in vitro. Methods: Human breastmilk from healthy donors (n = 7) was pooled and incubated with breast cancer (MCF-7 and MDA-MB-231) and macrophage (RAW264.7) cell lines to assess cell proliferation, viability, migration, and expression of key genes associated with epithelial-mesenchymal transition (EMT) and macrophage phenotype. Indirect co-culture studies assessed the effect of breastmilk on interactions between breast cancer cells and macrophages. Results: Breastmilk increased the proliferation and viability of breast cancer cells, reduced EMT markers, and reduced cell migration in MDA-MB-231 cells. Breastmilk decreased mRNA expression of interleukin 1B (IL1B) and interleukin 10 (IL10) in macrophages. Reduced EMT marker expression was observed in breast cancer cells co-cultured with macrophages pre-treated with breastmilk. Macrophages co-cultured with breast cancer cells pre-treated with breastmilk exhibited increased expression of a pro-inflammatory cytokine tumor necrosis factor A (TNFA) and pro-inflammatory nitric oxide synthase 2 (NOS2), and reduced expression of cytokines IL10 and transforming growth factor B1 (TGFB1) which are associated with the alternatively-activated macrophage phenotype. Conclusions: Breastmilk has the potential to promote breast cancer proliferation, however, it can also reduce breast cancer progression through inhibition of breast cancer cell migration and regulation of macrophage polarisation. These findings suggest that breastmilk has potential to shape the tumour microenvironment in postpartum breast cancer.

α-Parvin Expression in Breast Cancer Tissues: Correlation with Clinical Parameters and Prognostic Significance.

Stromal cells play a critical role in the tumor microenvironment of breast cancer (BC), as they are recruited by tumor cells and regulate the metastatic spread. Though high expression of α-parvin, a member of the parvin family of actin-binding proteins, is reported to be associated with a poor prognosis and metastasis in several cancers, its role in carcinogenesis has not been thoroughly explored. Therefore, we aimed to examine the expression of α-parvin in BC patients by compartmentalizing and quantifying tissues to determine whether α-parvin can be a potential therapeutic target. We performed immunohistochemical (IHC) staining of α-parvin in BC tissues, and the IHC scores were calculated in the overall tissue, stroma, and epithelium using image analysis software. The expression of α-parvin was significantly higher in BC tissues (p = 0.0002) and BC stroma (p < 0.0001) than in normal tissues. Furthermore, all α-parvin scores were significantly positively correlated with the proliferation marker Ki67. The overall and stroma scores are associated with the tumor, (lymph) node, and metastasis (TNM) classification, stage, and grade. These results suggest that high expression of α-parvin in stroma is associated with BCs and might be a new predictive marker for diagnosing BC.

Single-cell RNA-sequencing reveals a unique landscape of the tumor microenvironment in obesity-associated breast cancer

Single-cell RNA-sequencing reveals a unique landscape of the tumor microenvironment in obesity-associated breast cancer

Tumour immune characterisation of primary triple-negative breast cancer using automated image quantification of immunohistochemistry-stained immune cells

The tumour immune microenvironment (TIME) in breast cancer is acknowledged with an increasing role in treatment response and prognosis. With a growing number of immune markers analysed, digital image analysis may facilitate broader TIME understanding, even in single-plex IHC data. To facilitate analyses of the latter an open-source image analysis pipeline, Tissue microarray MArker Quantification (TMArQ), was developed and applied to single-plex stainings for p53, CD3, CD4, CD8, CD20, CD68, FOXP3, and PD-L1 (SP142 antibody) in a 218-patient triple negative breast cancer (TNBC) cohort with complementary pathology scorings, clinicopathological, whole genome sequencing, and RNA-sequencing data. TMArQ’s cell counts for analysed immune markers were on par with results from alternative methods and consistent with both estimates from human pathology review, different quantifications and classifications derived from RNA-sequencing as well as known prognostic patterns of immune response in TNBC. The digital cell counts demonstrated how immune markers are coexpressed in the TIME when considering TNBC molecular subtypes and DNA repair deficiency, and how combination of immune status with DNA repair deficiency status can improve the prognostic stratification in chemotherapy treated patients. These results underscore the value and potential of integrating TIME and specific tumour intrinsic alterations/phenotypes for the molecular understanding of TNBC.

PANoptosis-related molecular clustering and prognostic signature associated with the immune landscape and therapy response in breast cancer.

Breast cancer (BC) remains one of the most pervasive and complex malignancies. PANoptosis represents a recently identified cellular mechanism leading to programmed cell death. However, the prognostic implications and influence on the immune microenvironment of BC pertaining to PANoptosis-related genes (PRGs) remain significantly understudied. We conducted differential expression analysis to identify prognostic-Related PRGs by the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Next, we identified the PANoptosis-related molecular subtype using the consensus clustering analysis, and constructed and validated the PANoptosis-related prognostic signature using LASSO and Cox regression analyses. ROC curves were employed to assess the performance of the signatures. Furthermore, drug sensitivity between low- and high-risk group were analysis. Finally, we conducted RT-qPCR to assess the gene expression levels involved in this signature. We categorized BC patients into 2 distinct molecular clusters based on PRGs and identified differentially expressed genes associated with prognosis. Subsequently, BC patients were then divided into 2 gene clusters. The identified PRGs molecular clusters and gene clusters demonstrated association with patient survival, immune system functions, and biological processes and pathways of BC. A prognostic signature comprising 5 genes was established, and BC patients were classified into low- and high-risk groups based on the risk scores. The ROC curves demonstrated that those in the low-risk category exhibited notably extended survival compared to the high-risk group. A nomogram model for patient survival was constructed based on the risk score in conjunction with other clinical features. High-risk group had higher tumor burden mutation, CSC index and lower StomalScore, ImmuneScore, and ESTIMATEScore. Subsequently, we established a correlation between the risk score and drug sensitivity among BC patients. Finally, qRT-PCR results showed that the expression of CXCL1, PIGR, and TNFRSF14 significantly decreased, while CXCL13 and NKAIN were significantly increased in BC tissues. We have developed a molecular clustering and prognostic signature based on PANoptosis to improve the prediction of BC prognosis. This discovery has the potential to not only assist in assessing overall patient prognosis but also to deepen our understanding of the underlying mechanisms of PANoptosis in BC pathogenesis.

Exosome-mediated transfer of lncRNA RP3-340B19.3 promotes the progression of breast cancer by sponging miR-4510/MORC4 axis

BackgroundThis study aims to explore the molecular mechanism of lncRNA RP3-340B19.3 on breast cancer cell proliferation and metastasis and clinical significance of lncRNA RP3-340B19.3 for breast cancer.MethodsThe subcellular localization of lncRNA RP3-340B19.3 was identified using RNA fluorescence in situ hybridization (FISH). The expression of lncRNA RP3-340B19.3 in breast cancer cells, breast cancer tissues, as well as the serum and serum exosomes of breast cancer patients, was measured through quantitative RT-PCR. In the in vitro setting, we conducted experiments to observe the effects of RP3-340B19.3 on both cell migration and proliferation. This was achieved through the utilization of transwell migration assays as well as clone formation assays. Meanwhile, transwell migration assays and clone formation assays were used to observe the effects of MDA-MB-231-exosomes enriched in RP3-340B19.3 on breast cancer microenvironment cells MCF7 and BMMSCs. Additionally, western blotting techniques were used to assess the expression levels of proteins associated with essential cellular processes such as proliferation, apoptosis, and metastasis. In vivo, the impact of RP3-340B19.3 knockdown on tumour weight and volume was observed within a nude mice model. We aimed to delve into the intricate molecular mechanisms involving RP3-340B19.3 by using bioinformatics analysis, dual luciferase reporter gene experiments and western blotting. Moreover, the potential correlations between RP3-340B19.3 expression and various clinical pathological characteristics were analyzed.ResultsOur investigation revealed that RP3-340B19.3 was expressed in both the cytoplasm and nucleus, with a noteworthy increase in breast cancer cells. Notably, we found that RP3-340B19.3 exerted a promoting influence on the proliferation and migration of breast cancer cells, both in vitro and in vivo. MDA-MB-231-exosomes enriched in RP3-340B19.3 promoted the proliferation and migration of MCF7 and BMMSCs in vitro. Mechanistically, RP3-340B19.3 demonstrated the capability to modulate the expression of MORC4 by forming a complex with miR-4510. This interaction subsequently triggered the activation of the NF-κB and Wnt-β-catenin signaling pathways. Furthermore, our study highlighted the potential diagnostic utility of RP3-340B19.3. We discovered its presence in the serum and exosomes of breast cancer patients, showing promising efficacy as a diagnostic marker. Notably, the diagnostic potential of RP3-340B19.3 was particularly significant in relation to distinguishing between different pathological types of breast cancer and correlating with tumour diameter.ConclusionOur findings establish that RP3-340B19.3 plays a pivotal role in driving the proliferation and metastasis of breast cancer. Additionally, exosomes enriched in RP3-340B19.3 could influence MCF7 and BMMSCs in tumour microenvironment, promoting the progression of breast cancer. This discovery positions RP3-340B19.3 as a prospective novel candidate for a tumour marker, offering substantial potential in the realms of breast cancer diagnosis and treatment strategies.

Unconventional p65/p52 NF-κB module regulates key tumor microenvironment-related genes in breast tumor-associated macrophages (TAMs)

The complex heterogeneity of tumor microenvironment (TME) of triple-negative breast cancer (TNBC) presents a significant obstacle to cytotoxic immune response and successful treatment, building up one of the most hostile oncological phenotypes. Among the most abundant TME components, tumor-associated macrophages (TAMs) have pivotal pro-tumoral functions, involving discordant roles for the nuclear factor kappa-B (NF-κB) transcription factors and directing to higher levels of pathway complexity.In both resting macrophages and TAMs, we recently revealed the existence of the uncharacterized NF-κB p65/p52 dimer. In the present study, we demonstrated its enhanced active nuclear localization in TAMs and validated selected immune target genes as directly regulated by dimer binding on DNA sequences.We demonstrated by ChIP-qPCR that p65/p52 enrichment on HSPG2 and CSF-1 regulatory regions is strictly dependent on macrophage polarization and tumor environment.Our data provide novel mechanisms of transcriptional regulation in TAMs, orchestrated by the varied and dynamic nature of NF-κB combinations, which needs to be considered when targeting this pathway in cancer therapies.Our results offer p65/p52, together with identified regulatory regions on genes impacting macrophage behavior and tumor biology, as novel molecular targets for TNBC, aimed at modulating TAMs functions towards anti-tumoral phenotypes and thus improving cancer treatment outcomes.

Pan-Cancer Screening and Validation of CALU's Role in EMT Regulation and Tumor Microenvironment in Triple-Negative Breast Cancer.

Cancer-associated fibroblasts (CAFs) significantly contribute to tumor progression and the development of resistance to therapies across a range of malignancies, notably breast cancer. This study aims to elucidate the specific role and prognostic relevance of CALU across multiple cancer types. The association between CALU expression and prognosis, along with clinical characteristics in BRCA, HNSC, KIRP, LGG, and LIHC, was analyzed using data from the TCGA, GTEx, and GEO databases. Transcriptomic analysis of TCGA BRCA project data provided insights into the interaction between CALU and epithelial-mesenchymal transition (EMT) marker genes. Using TIMER and TISCH databases, the correlation between CALU expression and tumor microenvironment infiltration was assessed, alongside an evaluation of CALU expression across various cell types. Furthermore, CALU's influence on TNBC BRCA cell lines was explored, and its expression in tumor tissues was confirmed through immunohistochemical analysis of clinical samples. This study revealed a consistent upregulation of CALU across several tumor types, including BRCA, KIRP, LIHC, HNSC, and LGG, with elevated CALU expression being associated with unfavorable prognoses. CALU expression was particularly enhanced in clinical contexts linked to poor outcomes. Genomic analysis identified copy number alterations as the principal factor driving CALU overexpression. Additionally, a positive correlation between CALU expression and CAF infiltration was observed, along with its involvement in the EMT process in both CAFs and malignant cells. In vitro experiments demonstrated that CALU is highly expressed in TNBC-BRCA cell lines, and knockdown of CALU effectively reversed EMT progression and inhibited cellular migration. Immunohistochemical analysis of clinical samples corroborated the elevated expression of CALU in tumors, along with alterations in EMT markers. This comprehensive pan-cancer analysis underscores CALU's critical role in modulating the tumor microenvironment and facilitating cell migration via the EMT pathway, identifying it as a potential therapeutic target.

Decreased Expression of CD247 and CD4 Immune Marker Predicts Poor Prognosis in Triple Negative Breast Cancer.

Triple negative breast cancer (TNBC) is an aggressive from of breast cancer and is associated with poor prognosis. Tumor microenvironment of breast cancer consists of a wide range of cell types, including tumor-infiltrating lymphocytes (TILs). Accumulating evidence indicate that TILs play a crucial role in cancer progression and resistance to standard chemotherapy. We used online computational tools to evaluate the prognostic significance of CD247 and CD4 in TNBC. TNBC patients with lower expression of CD247 and CD4 have much shorter relapse- free survival and overall survival than the patients with higher expression of these genes. CD247 and CD4 expression show a strong positive correlation with tumor-infiltrating dendritic cells, B-cells, CD4+, CD8+, and neutrophils. We've concluded that low levels of CD247 and CD4 may stop immune cells from entering the area around the tumor, which stops cancer cells from being killed and gives the patient a bad outlook. These findings suggest that CD247 and CD4 may be useful biomarkers or as a target to understand the progression of TNBC. Our findings also suggest that CD247 and CD4 targeted therapeutics should be explored in detail, and could be a potentially used as atreatment strategy for TNBC.

Non-genomic effects of thyroid hormones on the breast cancer microenvironment

Non-genomic effects of thyroid hormones on the breast cancer microenvironment

PLGA Nanoplatform for the Hypoxic Tumor Delivery: Folate Targeting, Therapy, and Ultrasound/Photoacoustic Imaging.

Effective targeting of breast tumors is critical for improving therapeutic outcomes in breast cancer treatment. Additionally, hypoxic breast cancers are difficult to treat due to resistance toward chemotherapeutics, poor vascularity, and enhanced angiogenesis, which complicate effective drug delivery and therapeutic response. Addressing this formidable challenge requires designing a drug delivery system capable of targeted delivery of the anticancer agent, inhibition of efflux pump, and suppression of the tumor angiogenesis. Here, we have introduced Palbociclib (PCB)-loaded PLGA nanoparticles (NPs) consisting of chitosan-folate (CS-FOL) for folate receptor-targeted breast cancer therapy. The developed NPs were below 219 nm with a smooth, spherical surface shape. The entrapment efficiencies of NPs were achieved up to 85.78 ± 1.8%. Targeted NPs demonstrated faster drug release at pH 5.5, which potentiated the therapeutic efficacy of NPs due to the acidic microenvironment of breast cancer. In vitro cellular uptake study in MCF-7 cells confirmed the receptor-mediated endocytosis of targeted NPs. In vivo ultrasound and photoacoustic imaging studies on rats with hypoxic breast cancer showed that targeted NPs significantly reduced tumor growth and hypoxic tumor volume, and suppressed angiogenesis.

A cuproptosis-based nanomedicine suppresses triple negative breast cancers by regulating tumor microenvironment and eliminating cancer stem cells

Cuproptosis is a new kind of cell death that depends on delivering copper ions into mitochondria to trigger the aggradation of tricarboxylic acid (TCA) cycle proteins and has been observed in various cancer cells. However, whether cuproptosis occurs in cancer stem cells (CSCs) is unexplored thus far, and CSCs often reside in a hypoxic tumor microenvironment (TME) of triple negative breast cancers (TNBC), which suppresses the expression of the cuproptosis protein FDX1, thereby diminishing anticancer efficacy of cuproptosis. Herein, a ROS-responsive active targeting cuproptosis-based nanomedicine CuET@PHF is developed by stabilizing copper ionophores CuET nanocrystals with polydopamine and hydroxyethyl starch to eradicate CSCs. By taking advantage of the photothermal effects of CuET@PHF, tumor hypoxia is overcome via tumor mechanics normalization, thereby leading to enhanced cuproptosis and immunogenic cell death in 4T1 CSCs. As a result, the integration of CuET@PHF and mild photothermal therapy not only significantly suppresses tumor growth but also effectively inhibits tumor recurrence and distant metastasis by eliminating CSCs and augmenting antitumor immune responses. This study presents the first evidence of cuproptosis in CSCs, reveals that disrupting hypoxia augments cuproptosis cancer therapy, and establishes a paradigm for potent cancer therapy by simultaneously eliminating CSCs and boosting antitumor immunity.

Light-activated hypoxia-sensitive biomimetic decoy efficiently cascading photodynamic-chemo therapy for breast cancer

The hypoxic microenvironment within the tumor microenvironment of breast cancer imposes a challenge in overcoming chemotherapy resistance. In this investigation, we designed a novel strategy utilizing a light-controlled cascade targeting nanomedicine specifically tailored for enhanced immune therapy of breast cancer. Albumin nanoparticle was achieved by crosslinking, followed by loading TPZ and Ce6, and subsequent modification to enable selective binding with CD44 hyaluronic acid to form nanomedicine. Encouragingly, it was demonstrated the remarkable ability of the nanomedicine to effectively internalize into cellular entities, thereby inducing apoptosis in 4T1 cells efficiently in vitro when exposed to light irradiation. In vivo assessments showcased the exceptional aptitude of the nanomedicine not only for preferential accumulation within tumor tissues, but also for substantial suppression of tumor growth. Immune mechanisms have shown that nanomedicine treatment promoted the maturation of DCs in vivo, enhanced the proportion of CD8+ T cells in the spleen and tumor, and simultaneously upregulated the ratio of M1 macrophages favorable for anti-tumor effects. These outcomes collectively advance a fresh perspective for the clinical breast cancer therapy.

Inflammatory breast cancer microenvironment repertoire based on DNA methylation data deconvolution reveals actionable targets to enhance the treatment efficacy

BackgroundAlthough the clinical signs of inflammatory breast cancer (IBC) resemble acute inflammation, the role played by infiltrating immune and stromal cells in this aggressive disease is uncharted. The tumor microenvironment (TME) presents molecular alterations, such as epimutations, prior to morphological abnormalities. These changes affect the distribution and the intricate communication between the TME components related to cancer prognosis and therapy response. Herein, we explored the global DNA methylation profile of IBC and surrounding tissues to estimate the microenvironment cellular composition and identify epigenetically dysregulated markers.MethodsWe used the HiTIMED algorithm to deconvolve the bulk DNA methylation data of 24 IBC and six surrounding non-tumoral tissues (SNT) (GSE238092) and determine their cellular composition. The prognostic relevance of cell types infiltrating IBC and their relationship with clinicopathological variables were investigated. CD34 (endothelial cell marker) and CD68 (macrophage marker) immunofluorescence staining was evaluated in an independent set of 17 IBC and 16 non-IBC samples.ResultsWe found lower infiltration of endothelial, stromal, memory B, dendritic, and natural killer cells in IBC than in SNT samples. Higher endothelial cell (EC) and stromal cell content were related to better overall survival. EC proportions positively correlated with memory B and memory CD8+ T infiltration in IBC. Immune and EC markers exhibited distinct DNA methylation profiles between IBC and SNT samples, revealing hypermethylated regions mapped to six genes (CD40, CD34, EMCN, HLA-G, PDPN, and TEK). We identified significantly higher CD34 and CD68 protein expression in IBC compared to non-IBC.ConclusionsOur findings underscored cell subsets that distinguished patients with better survival and dysregulated markers potentially actionable through combinations of immunotherapy and epigenetic drugs.

Bibliometric analysis of global research trends between gut microbiota and breast cancer: from 2013 to 2023.

Breast cancer is the most prevalent cancer globally and is associated with significant mortality. Recent research has provided crucial insights into the role of gut microbiota in the onset and progression of breast cancer, confirming its impact on the disease's management. Despite numerous studies exploring this relationship, there is a lack of comprehensive bibliometric analyses to outline the field's current state and emerging trends. This study aims to fill that gap by analyzing key research directions and identifying emerging hotspots. Publications from 2013 to 2023 were retrieved from the Web of Science Core Collection database. The VOSviewer, R language and SCImago Graphica software were utilized to analyze and visualize the volume of publications, countries/regions, institutions, authors, and keywords in this field. A total of 515 publications were included in this study. The journal Cancers was identified as the most prolific, contributing 21 papers. The United States and China were the leading contributors to this field. The University of Alabama at Birmingham was the most productive institution. Peter Bai published the most papers, while James J. Goedert was the most cited author. Analysis of highly cited literature and keyword clustering confirmed a close relationship between gut microbiota and breast cancer. Keywords such as "metabolomics" and "probiotics" have been prominently highlighted in the keyword analysis, indicating future research hotspots in exploring the interaction between metabolites in the breast cancer microenvironment and gut microbiota. Additionally, these keywords suggest significant interest in the therapeutic potential of probiotics for breast cancer treatment. Research on the relationship between gut microbiota and breast cancer is expanding. Attention should be focused on understanding the mechanisms of their interaction, particularly the metabolite-microbiota-breast cancer crosstalk. These insights have the potential to advance prevention, diagnosis, and treatment strategies for breast cancer. This bibliometric study provides a comprehensive assessment of the current state and future trends of research in this field, offering valuable perspectives for future studies on gut microbiota and breast cancer.

Contribution of pre-diagnostic host factors to shaping the stromal microenvironment of breast cancer among sub-Saharan African women.

The stromal microenvironment (SME) is integral to breast cancer (BC) biology, impacting metastatic proclivity and treatment response. Emerging data indicate that host factors may impact the SME, but the relationship between pre-diagnostic host factors and SME phenotype remains poorly characterized, particularly among women of African ancestry. We conducted a case-only analysis involving 792 BC patients (17-84 years) from the Ghana Breast Health Study (GBHS). High-accuracy machine-learning algorithms were applied to standard H&E-stained images to characterize SME phenotypes (including percent tumor-associated connective tissue stroma, Ta-CTS (%), and tumor-associated stromal cellular density, Ta-SCD (%)). Associations between pre-diagnostic host factors and SME phenotypes were assessed in multivariable linear regression models. Decreasing Ta-CTS and increasing Ta-SCD were associated with aggressive, mostly high-grade tumors (p-value<0.001). Several pre-diagnostic host factors were associated with Ta-SCD independently of tumor characteristics. Compared with nulliparous women, parous women had higher levels of Ta-SCD [mean (standard deviation, SD) = 31.3% (7.6%) vs. 28.9% (7.1%); p-value=0.01]. Similarly, women with a positive family history of breast cancer had higher levels of Ta-SCD than those without family history [mean (SD) = 33.0% (7.5%)] vs. 30.9% (7.6%); p-value=0.03]. Conversely, increasing body size was associated with decreasing Ta-SCD [mean (SD) = 32.0% (7.4%), 31.3% (7.3%), and 29.0% (8.0%) for slight, average, and large body sizes, respectively, p-value=0.005]. Epidemiological risk factors were associated with varying degrees of stromal cellularity in tumors, independently of clinicopathological characteristics. The findings raise the possibility that epidemiological risk factors may partly influence tumor biology via the SME.