Breast cancer (BC) is the leading cause of cancer death in women, with hormone-dependent BC accounting for about 80 % of cases, primarily affecting postmenopausal women with gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) elevated. Treatments targeting the gonadotropin-releasing hormone receptor (GnRHR), such as the agonist leuprorelin (LEU) and antagonist degarelix (DEGA), are used for hormone-dependent tumors. While the functional role of gonadotropin receptors in extragonadal tissues remains uncertain, recent studies suggest LH contributes to tumor development and progression. Tumor progression involves reorganization in the actin cytoskeleton, induction of adhesion, and cell migration, driven by proteins such as Src and the focal adhesion kinase (FAK), which are related to invasive behaviors. The overexpression of both protein kinases generates an invasive and metastatic phenotype, then inhibitors targeting Src (PP2) and FAK (FAKi) have been developed to counteract this effect. This study combined GnRH analogs with Src and FAK inhibitors to target BC progression. We found that LH treatment influenced gene expression linked to tumor development. Examining the GnRHR-LEU and GnRHR-DEGA complexes revealed structural differences affecting ligand binding. In an orthotopic tumor model, DEGA reduced tumor growth, while LEU had the opposite effect. Combining DEGA with PP2 or FAKi enhanced tumor inhibition, improving mice survival. These findings provide valuable insights into the essential regulatory role of gonadotropins in genes involved in tumorigenic processes, highlighting the potential of GnRHR antagonists combined with Src or FAK inhibitors as a promising strategy to develop new drugs that interfere with the ability of breast tumor progression.

Immunotherapy is a potential strategy to suppress the postoperative recurrence and metastasis of triple-negative breast cancer (TNBC). However, the excessive accumulation of kynurenine (Kyn) leads to immunosuppressive tumor microenvironment (TME) and impedes immunotherapeutic efficacy. Herein, a two-pronged approach through "Kynurenine Starvation Therapy" is proposed based on the in-situ hydrogel implantation for postsurgical treatment of TNBC. The hydrogel is constructed via Schiff base reaction between oxidized dextran (ODEX) and 8-arm poly(ethylene glycol) amine (8-arm PEG-NH2), which exhibits excellent biocompatibility and gradual biodegradability. The indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor NLG919 and kynureninase (KYNase) are noncovalently loaded into the hydrogel to prepare NLG919 + KYNase@Gel. The obtained hydrogel can sustainably release NLG919 and KYNase to synergistically deplete Kyn, thereby reversing immunosuppression to enhance the antitumor immunity within TME through "Kynurenine Starvation Therapy". Moreover, a single implantation of NLG919 + KYNase@Gel not only effectively inhibits the postoperative recurrence and metastasis in 4 T1 tumor-bearing mice, but also restrains the growth in an orthotopic TNBC mouse model. These findings highlight an innovative strategy to reinforce the antitumor immune response for the treatment of postsurgical TNBC.

Bone metastasis is a leading cause of mortality in breast cancer patients. Monitoring biomarkers for bone metastasis in breast cancer is crucial for the development of effective interventional treatments. Despite being a highly vascularized tissue, the bone presents a particularly hypoxic environment. Tumor hypoxia is closely linked to increased levels of various reductases, including nitroreductase (NTR). Currently, there are few probes available to detect NTR levels in breast cancer bone metastases. Although bioluminescent imaging is promising due to its specificity and high signal-to-noise ratio, many probes face challenges such as short emission wavelengths, reliance on complex conditions like external adenosine triphosphate, or lack of tissue specificity. In this study, through "caging" the luciferase substrate with an NTR-responsive aromatic nitro recognition group, we developed a highly sensitive and selective NTR-sensitive bioluminescent probe. The resulting probe effectively detects NTR in breast cancer cells and enables real-time monitoring of NTR in a mouse model of breast cancer bone metastasis. Additionally, it can differentiate between primary and bone tumors, and allow continuous monitoring of NTR levels, thus providing valuable insights into bone tumor progression. This work provides a powerful tool for further understanding the biological functions of NTR in breast cancer bone metastasis.

Breast cancer, particularly metastatic breast cancer (MBC), presents aggressive clinical challenges with limited treatment success. Immunotherapy has emerged as a promising approach, however, discrepancies between preclinical animal models and human cancers complicate translation to clinical outcomes. This systematic review and meta-analysis evaluated the effect of immunotherapy on primary and metastatic tumor regression in animal models of MBC and assessed the models' appropriateness and reproducibility to improve future preclinical study design. Following a preregistered protocol in PROSPERO (CRD42021207033), we conducted searches in MEDLINE, Embase, and Web of Science databases, yielding 2255 studies for title/abstract screening and 108 studies included after full-text screening. All included studies used mouse models, assessing primary outcomes through tumor volume or weight and metastatic outcomes via nodule count or bioluminescence. Only 14% of studies fully reported experimental animal characteristics, and 43% provided detailed experimental procedures. Of 105 articles (293 comparisons) included in the meta-analysis, pooled effect sizes indicated significant reductions in both primary and metastatic tumors. However, high heterogeneity across studies and wide prediction intervals suggested substantial variability in model responses to immunotherapy. Univariable and multivariable meta-regressions failed to significantly explain this heterogeneity, suggesting additional factors may influence outcomes. Trim-and-fill and Egger's regression tests indicated funnel plot asymmetry, implying potential publication bias and small study effects. While our analysis demonstrated positive effects of immunotherapy on MBC and highlighted variability in animal tumor models, addressing model-related heterogeneity and enhancing methodological transparency are essential to improve reproducibility and clinical translatability.

Breast cancer cells frequently exhibit changes in the expression of nuclear envelope (NE) proteins such as lamins and emerin that determine the physical properties of the nucleus and contribute to cellular mechanotransduction. This review explores the emerging interplay between NE proteins, the physical challenges incurred during metastatic progression, and mechanotransduction. Improved insights into the underlying mechanisms may ultimately lead to better prognostic tools and treatment strategies for metastatic breast cancer.

Breast cancer (BC) is a significant global cause of death in women, primarily due to its diversity and metastatic potential.

BC, healthy lymph node (HL), and metastatic lymph node (ML) tissues were collected from 19 patients diagnosed with infiltrating ductal carcinoma. Protein isolation was performed, followed by two-dimensional gel electrophoresis (2DE) and mass spectrometry (MALDI-TOF/TOF) to identify differentially expressed proteins. Bioinformatic analyses, including protein-protein interaction networks and molecular pathways, were conducted using STRING. Kaplan-Meier analysis was performed with KM plotter to evaluate the prognostic significance of identified proteins. Receiver operating characteristic (ROC) curves were generated using TCGA and GTEx data from UCSC Xena and easyROC to assess diagnostic relevance.

Distinct pathways related to cytoskeletal regulation, immune modulation, and oxidative stress response were enriched in each subtype. Key proteins such as TUBA1C, CCT6A, and Vimentin (LNA), CAPZB and ENO1 (LNB), GSTO1 (HER2 OE), and CORO1A and LAP3 (TNBC) were identified as significant in driving metastatic behavior. KM survival analysis showed that CAPZB (LNB) and CORO1A (TNBC) were associated with patient outcomes, while GSTO1 was linked to improved distant metastasis-free survival in HER2 OE. ROC analysis highlighted CAPZB as a strong diagnostic marker.

These findings form a basis for comprehending the molecular mechanisms underlying metastasis in different subtypes of breast cancer. They may lead to the identification of new therapeutic targets for customized interventions against invasion and metastasis. Further validation is required to confirm their clinical utility in larger cohorts.

Breast cancer (BC) has the second highest incidence rate among women worldwide. Although there are various treatment methods, the prognosis is poor once metastasis occurs. However, the extent to which pathogens of infectious diseases influence the risk of BC remains unclear. The goal of this study is to determine if these pathogens are causally related to BC development. A Mendelian randomization (MR) analysis is used to assess the causal relationship between infectious pathogen antibodies and the risk of BC, as well as their potential intermediary factors. Two-sample MR analysis using inverse variance weighting (IVW) is conducted to determine the causal relationship between infectious pathogen antibodies and the risk of BC. Additionally, the mediating role of 1400 metabolites between infectious pathogen antibodies and the risk of BC is analyzed. There were 5 infectious pathogen antibodies and 86 metabolites associated with BC (P < .05). There were 14 metabolites that mediated the pathway between infectious pathogen antibodies and BC. X-07765 levels showed a significant negative mediating effect on the relationship between Anti-human herpes virus 6 IgG seropositivity and BC (beta = -0.0025, 95% CI [-0.0046, -0.0003], P = .0236), accounting for 14.8% of the effect (95% CI: 27.7-1.99). This study provides a thorough evaluation of the causal relationships among infectious pathogen antibodies, plasma metabolites, and BC. Our research has identified 5 infectious pathogen antibodies that exhibit a causal relationship with BC, mediated through 86 distinct metabolites.

Unique from the other tumor cells, tumorigenic cancer stem cells (CSCs) manifest as a subpopulation of cells within the tumor that exhibit genetic and phenotypic features and signaling processes, which escape traditional anti-oncogenic treatments, thereby triggering metastases and relapses of cancers. Critical to cancer biology is the crosstalk between CSCs and tumor microenvironment (TME), implicating a CSC-based cancer immunotherapy. Cognizant of CSCs' significant role in cancer pathology and treatment, finding a biological model that recapitulates CSCs and TME may allow a better understanding of tumor onset and progression for testing CSC-based therapies. In this review paper, we examined the CSC and TME characteristics of the human embryonal carcinoma NTERA-2 clonal cell line called NTERA-2 cl.D1 or NT2/D1 cells and discussed their potential utility for research and development of treatments for cancer and central nervous system (CNS) disorders.

To probe our hypotheses that NT2/D1 cells display CSC and TME properties key to tumor development, which can serve as a screening platform to test cancer and CNS therapeutics, we conducted a literature review over a 10-year period (2014-2024), focusing on PUBMED and Science Direct published articles on cellular models of cancer, with emphasis on milestone research discoveries on NT2/D1 cells relevant to CSCs and TME. We categorized the studies under pre-clinical and clinical investigations in supporting the existence of CSC and TME features in NT2/D1 cells and providing a laboratory-to-clinic translational basis for cancer and CNS therapeutics.

NT2/D1 cells stand as a feasible biological model that recapitulates the crosstalk of CSCs and TME, which may critically contribute to our understanding of cancer and CNS biology and therapeutics. Designing therapeutics against CSCs' distinct self-renewal and differentiation capacities within the TME opens new avenues for treating cancers and CNS disorders.

The relationship between cytokines and lung metastasis (LM) in breast cancer (BC) remains unclear and current clinical methods for identifying breast cancer lung metastasis (BCLM) lack precision, thus underscoring the need for an accurate risk prediction model. This study aimed to apply machine learning algorithms for identifying the key risk factors for BCLM before developing a reliable prediction model centered on cytokines.

This population-based retrospective study included 326 BC patients admitted to the Second Affiliated Hospital of Xuzhou Medical University between September 2018 and September 2023. After randomly assigning the patients to a training cohort (70%; n = 228) or a validation cohort (30%; n = 98) the risk factors for BCLM were identified using Least Absolute Shrinkage and Selection Operator (LASSO), Extreme Gradient Boosting (XGBoost) and Random Forest (RF) models. Significant risk factors were visualized with a Venn diagram and incorporated into a nomogram model, the performance of which was then evaluated according to three criteria, namely discrimination, calibration and clinical utility using calibration plots, receiver operating characteristic (ROC) curves and decision curve analysis (DCA).

Among the cohort, 70 patients developed LM. A nomogram was then developed to predict the 5-year and 10-year BCLM risk by incorporating five key variables, namely endocrine therapy, hsCRP, IL6, IFN-ɑ and TNF-ɑ. For the 5-year prediction model, the training and validation cohorts had AUC values of 0.786 (95% CI: 0.691-0.881) and 0.627 (95% CI: 0.441-0.813), respectively, while for the 10-year prediction model, the corresponding AUC values were 0.687 (95% CI: 0.528-0.847) and 0.797 (95% CI: 0.605-0.988), respectively. ROC analysis further confirmed the model's strong discriminative ability, while calibration plots indicated that the predicted and observed outcomes were in good agreement in both cohorts. Finally, DCA demonstrated the model's effectiveness in clinical practice.

Using machine learning algorithms, this study developed aa nomogram that could effectively identify BC patients who were at a higher risk of developing LM, thus providing a valuable tool for decision-making in clinical settings.

Breast cancer is the primary cause of cancer-related death and the most frequent malignancy among women in Western countries. Although there have been advancements in combination treatments and targeted therapies for the metastatic diseases management, metastatic breast cancer is still the second most common cause of cancer-related deaths among U.S. women. The routes of metastasis encompass invasion, intravasation, circulation, extravasation, infiltration into a remote location to establish a metastatic niche, and the formation of micro-metastases in a new environment. Each of these processes is regulated by changes in gene expression. MicroRNAs (miRNAs) are widely expressed by a variety of organisms and have a key role in cell activities including suppressing or promoting cancer through regulating various pathways. Target gene expression is post-transcriptionally regulated by miRNAs, which contribute to the development, spread, and metastasis of breast cancer. In this study, we comprehensively discussed the role of miRNAs as predictors of breast cancer metastasis, their correlation with the spread of the disease to certain organs, and their potential application as targets for breast cancer treatment. We also provided molecular mechanisms of miRNAs in the progression of breast cancer, as well as current challenges in miRNA-based therapeutic approaches. Furthermore, as one of the primary issues with the treatment of solid malignancies is the efficient delivery of miRNAs, we examined a number of cutting-edge carriers for miRNA-based therapies and CRISPR/Cas9 as a targeted therapy for breast cancer.

Metastatic cancer is reported to have a mortality rate of 90%. Understanding the underlying principles of metastasis and quantifying them through mathematical modelling provides insights into potential treatment regimes. This work presents a partial differential equation based mathematical model embedded on a network, representing the organs and the blood vessels between them, with the aim of predicting likely secondary metastatic sites. Through this framework the relationship between metastasis and blood flow and between metastasis and the diffusive behaviour of cancer is explored. An analysis of the model predictions showed a good correlation with clinical data for some cancer types, particularly for cancers originating in the gut and liver. The model also predicts an inverse relationship between blood velocity and the concentration of cancer cells in secondary organs. Finally, for anisotropic diffusive behaviour, where the cancer experiences greater diffusivity in one direction, metastatic efficiency decreased. This is aligned with the clinical observation that gliomas of the brain, which typically show anisotropic diffusive behaviour, exhibit fewer metastases. The investigation yields some valuable results for clinical practitioners and researchers-as it clarifies some aspects of cancer that have hitherto been difficult to study, such as the impact of differing diffusive behaviours and blood flow rates on the global spread of cancer. The model provides a good framework for studying cancer progression using cancer-specific information when simulating metastasis.

Breast cancer stands as the most prevalent malignancy among the female populace. One of the pivotal domains in the therapeutic landscape of breast cancer revolves around the precise targeting of the p53-MDM2 inhibitory pathway. The advent of p53-MDM2 inhibition in the context of developing treatments for breast cancer marks a significant stride. In the quest for enhancing the efficacy of p53-MDM2 inhibition against breast cancer, a new series of benzothiazole compounds (B1-B30) was designed through in-silico methodologies in the present work. Using Schrodinger Maestro, the compounds underwent molecular docking assessments against the p53-MDM2 target (PDB: 4OGT). Compared to reference compounds, B25 and B12 exhibited notably elevated glide scores. Extensive in-silico studies, including ADMET and toxicity evaluations, were performed to predict pharmacokinetics, drug likeness, and toxicity. All compounds adhered to Lipinski criteria, signifying favorable oral drug properties. The MM-GBSA analysis indicated consistent binding free energies. Molecular dynamics simulations for B25 over 200 ns assessed complex stability and interactions. In summary, these compounds exhibit potential for future cancer therapy medication development.

Although only a fraction of tumor cells contribute to metastatic disease, no prognostic biomarkers currently exist to identify these cells. We show that a physical marker-adhesion strength-predicts metastatic potential in a mouse breast cancer model and that it may stratify human disease. Cells disseminating from murine mammary tumors are weakly adherent, and, when pre-sorted by adhesion, primary tumors created from strongly adherent cells exhibit fewer lung metastases than weakly adherent cells do. We demonstrate that admixed cancer lines can be separated by label-free adhesive signatures. When applied to murine metastatic tumors, adhesion retrospectively predicts metastatic disease with 100% specificity, 85% sensitivity, and area under the curve (AUC) of 0.94. Cells from human reduction mammoplasties have a higher adhesion strength versus resected human tumors, which may also be stratified between invasive and more indolent cancers. Thus, highly metastatic cells may have a distinct physical phenotype that may be a predictive marker of clinical outcomes.

To compare the outcomes of patients with pulmonary metastases from breast cancer, who were treated with transvenous pulmonary chemoembolization (TPCE) and consecutive microwave ablation (MWA) with patients treated by TPCE alone.

This retrospective single-center study included patients with unresectable and/or non-responsive to systemic chemotherapy pulmonary metastases originating from breast cancer, treated by TPCE followed by MWA, in case of adequate response to TPCE, or by TPCE alone. The groups of patients were balanced using propensity score matching (PSM).

A total of 97 patients met the inclusion criteria for this study. After PSM, 23 patients were included in the combination therapy group (Group 1) and 42 patients were included in the monotherapy group (Group 2). The median overall survival (OS) time was 33.6 months for Group 1 with a 2-year OS rate of 62%, and 20.2 months for Group 2 with a 2-year OS rate of 43%. There was no significant difference between the two groups regarding OS (p value: 0.429). The rate of progressive/recurrent disease was 17.4% (4/23) in Group 1 and 23.8% (10/42) in Group 2 (p value: 0.754). The number of metastases was the only significant factor for OS in all patients after PSM (p value: 0.032, HR: 1.016, 95% CI 1.001-1.031).

TPCE is an effective potential treatment for lung metastases of breast cancer, which can be performed alone or combined with MWA. Patients who responded to TPCE and received subsequent MWA demonstrated non-significant better OS and local tumor control.

Specific bacteria, including Fusobacterium nucleatum, Streptococcus sanguis, Enterococcus faecalis, and Staphylococcus xylosus, have been identified as contributors to breast cancer metastasis. Due to limitations such as lack of selectivity, traditional antibiotic therapies face obstacles in eliminating intratumoral bacteria. Herein, this work proposes the use of therapeutic vaccines to selectively target and eliminate harmful bacteria within tumors. A multivalent vaccine encapsulating both insoluble and soluble bacterial antigens was developed, addressing the shortcomings of traditional antibacterial vaccines by balancing broad antigen coverage with effective immune activation. This vaccine induces robust downstream immune responses to eliminate F. nucleatum, S. sanguis, E. faecalis, and S. xylosus, demonstrating notable therapeutic and preventive efficacy in bacteria-induced cancer metastasis models. Unexpectedly, vaccinated infected mice showed even slower tumor metastasis than uninfected mice. Overall, this study validates the potential of nanovaccines in modulating the intratumoral microbiome for tumor therapy and highlights tumor-associated bacterial infections as potential promising antitumor targets.

Tumor metastasis regulated by multiple complicated pathways is closely related to variations in the tumor microenvironment. Exosomes can regulate the tumor microenvironment through various mechanisms. Exosomes derived from tumor cells carry a variety of substances, including long non-coding RNAs (lncRNAs), play important roles in intercellular communication and act as critical determinants influencing tumor metastasis. In this review, we elaborate on several pivotal processes through which lncRNAs regulate tumor metastasis, including the regulation of epithelial‒mesenchymal transition, promotion of angiogenesis and lymphangiogenesis, enhancement of the stemness of tumor cells, and evasion of immune clearance. Additionally, we comprehensively summarized a diverse array of potential tumor-derived exosomal lncRNA biomarkers to facilitate accurate diagnosis and prognosis in a clinical setting.

Alpha-smooth muscle actin (α-SMA) expression in the stroma is linked to the presence of cancer-associated fibroblasts and is known to correlate with worse outcomes in various tumors. In this study, using a GeoMx digital spatial profiling approach, we characterized the gene expression of the tumor and α-SMA-expressing stromal cell compartments in pancreatic neuroendocrine tumors (PanNETs). The profiling was performed on tissues from eight retrospective cases (three grade 1, four grade 2, and one grade 3). Selected regions of interest were segmented geometrically based on tissue morphology and fluorescent signals from synaptophysin and α-SMA markers. The α-SMA-expressing stromal-cell-associated genes were involved in pathways of extracellular matrix modification, whereas, in tumor cells, the gene expression profiles were associated with pathways involved in cell proliferation. The comparison of gene expression profiles across all three PanNET grades revealed that the differences between grades are not only present at the level of the tumor but also in the α-SMA-expressing stromal cells. Furthermore, the tumor cells from regions with a rich presence of adjacent α-SMA-expressing stromal cells revealed an upregulation of matrix metalloproteinase-9 (MMP9) expression in grade 3 tumors. This study provides an in-depth characterization of gene expression profiles in α-SMA-expressing stromal and tumor cells, and outlines potential crosstalk mechanisms.

Lymph node metastasis (LNM) significantly affects the prognosis and clinical management of breast cancer (BC) patients. This systematic review and meta-analysis aim to identify microRNAs (miRNAs) associated with LNM in BC and evaluate their potential diagnostic and prognostic value. Following PRISMA guidelines, a comprehensive literature search was conducted in PubMed, Web of Science, and SCOPUS databases, to assess the role of miRNAs in LNM BC. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool was used to evaluate the quality of included studies. A total of 84 miRNAs were identified as differentially expressed in BC patients with LNM. Of these, a meta-analysis was performed in two microRNAs that were present in at least 3 different articles with a coherent expression direction: miR-155 and miR-34a. The meta-analysis returned a pooled a Log2 fold change of 1.50 for miR-155 (upregulated) and -0.53 for miR-34a (downregulated) with no evidence of publication bias, and a low risk of bias and applicability concerns. To conclude, this study names miR-155 and miR-34a as potential diagnostic biomarkers for LNM in BC, although further experimental validation is necessary to confirm these findings and develop non-invasive diagnostic tools for clinical use.

Breast cancer (BC) is the most diagnosed cancer worldwide, and patients' survival decreases with metastasis. We conducted a retrospective study using data derived from the Surveillance, Epidemiology, and End Results (SEER) database and clinicopathological data to construct a clinical predictive model to predict the risk and prognosis of lung metastasis (LM) in patients with different subtypes of BC and validate its performance.

A total of 1650 patients from the SEER database between 2011 and 2015 were enrolled in this study. Cox regression analysis was performed to identify prognostic factors for breast cancer lung metastasis (BCLM). A nomogram was constructed using the independent prognostic factors. The concordance index (C-index), area under the curve (AUC) value, calibration curve, and decision curve analysis (DCA) were used to test the prediction accuracy of the nomogram. External validation (n = 112) was performed using clinical data from the Affiliated Hospital of Qinghai University and the General Hospital of Ningxia Medical University.

Multivariate Cox regression analyses suggested that age, grade, surgery, chemotherapy, subtype, and liver, bone, and brain metastases were independent prognostic factors for overall survival (OS). Kaplan-Meier survival analysis showed that the median survival times of patients with human epidermal growth factor receptor 2 (HER2)-positive, luminal A, luminal B, and triple-negative BC were 25 (95% confidence interval [CI], 20-37), 27 (95% CI, 23-29), 35 (95% CI, 30-44), and 12 (95% CI, 11-14), respectively. The C-indexes of the nomogram for predicting OS of the SEER training, SEER validation, and clinical validation cohorts were 0.7, 0.6, and 0.6, respectively, and the calculated AUCs at 3 years were 0.765, 0.794, and 0.799, respectively. The calibration curve indicates that the nomogram possessed a high level of accuracy.

Our nomogram demonstrates significant predictive value, indicating that molecular subtypes, brain metastasis, and liver metastasis are closely associated with the prognosis of patients with LM. This information can guide clinical practice.

Although the number of breast cancer deaths has decreased, and there have been developments in targeted therapies and combination treatments for the management of metastatic illness, metastatic breast cancer is still the second most common cause of cancer-related deaths in U.S. women. Numerous phases and a vast number of proteins and signaling molecules are involved in the invasion-metastasis cascade. The tumor cells penetrate and enter the blood or lymphatic vessels, and travel to distant organs via the lymphatic or blood vessels. Tumor cells enter cell cycle arrest, adhere to capillary beds in the target organ, and then disseminate throughout the organ's parenchyma, proliferating and enhancing angiogenesis. Each of these processes is regulated by changes in the expression of different genes, in which lncRNAs play a role in this regulation. Transcripts that are longer than 200 nucleotides and do not translate into proteins are called RNAs. LncRNA molecules, whose function depends on their unique molecular structure, play significant roles in controlling the expression of genes at various epigenetic levels, transcription, and so on. LncRNAs have essential functions in regulating the expression of genes linked to cell development in healthy and pathological processes, specialization, programmed cell death, cell division, invasion, DNA damage, and spread to other parts of the body. A number of cancer types have been shown to exhibit aberrant expression of lncRNAs. In this review, we describe the general characteristics, potential molecular mechanisms and targeted therapy of lncRNAs and discuss the emerging functions of lncRNAs in breast cancer.

Paclitaxel (PTX) is a chemotherapeutic agent that is frequently used for breast cancer treatment, but it has been associated with promoting distant metastases, including to the lungs, liver, and bones. Shenhuang plaster (SHP), a traditional Chinese medicine, has shown potential for modulating the tumor microenvironment (TME). This study investigates whether a combination of SHP and PTX can enhance the anti-tumor efficacy of PTX and mitigate its pro-metastatic effects in a 4T1 breast cancer mouse model.

Female Balb/c mice were injected with 4T1 breast cancer cells and then divided into four treatment groups: control, PTX, SHP, and PTX+SHP. The combination of SHP and PTX was evaluated using bioluminescence imaging (BLI), histological analysis, and hematoxylin and eosin (HE) staining to assess lung metastasis. Flow cytometry was employed to analyze immune cell populations, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and cytotoxic T cells (CD8+ and CD4+).

SHP alone did not significantly inhibit lung metastasis but the combination of PTX and SHP led to a marked reduction in lung lesions, as confirmed by BLI and histological analysis. SHP improved the overall health of PTX-treated mice, reducing their body weight loss and mortality. Flow cytometry revealed that the combination therapy reduced the infiltration of M2 macrophages, MDSCs, and Tregs, while increasing the proportion of antitumor M1 macrophages, cytotoxic CD8+ T cells, and helper CD4+ T cells.

The combination of PTX and SHP has a synergistic effect, reducing lung metastasis and modulating immune cell populations within the TME. These results suggest that integrating traditional Chinese medicine with standard chemotherapy can enhance therapeutic efficacy and reduce adverse effects.

Neoadjuvant immunotherapy seeks to harness the primary tumor as a source of relevant tumor antigens to enhance systemic anti-tumor immunity through improved immunological surveillance. Despite having revolutionized the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC), a significant portion of patients remain unresponsive and succumb to metastatic recurrence post-treatment. Here, we found that optimally scheduled neoadjuvant administration of anti-4-1BB monotherapy was able to counteract metastases and prolong survival following surgical resection. Phenotypic and transcriptional profiling revealed enhanced 4-1BB expression on tumor-infiltrating intermediate (T int ), relative to progenitor (T prog ) and terminally exhausted (T term ) T cells. Furthermore, T int was enriched in low-affinity T cells. Treatment with anti-4-1BB drove clonal expansion of T int , with reduced expression of tissue-retention marker CD103 in T prog . This was accompanied by increased TCR clonotype sharing between paired tumors and pre-metastatic lungs. Further interrogation of sorted intratumor T cells confirmed enhanced T cell egress into circulation following anti-4-1BB treatment. In addition, gene signature extracted from anti-4-1BB treated T int was consistently associated with improved clinical outcomes in BRCA patients. Combinatorial neoadjuvant anti-4-1BB and ablation of tumor-derived CXCL16 resulted in enhanced therapeutic effect. These findings illustrate the intratumor changes underpinning the efficacy of neoadjuvant anti-4-1BB, highlighting the reciprocity between local tissue-retention and distant immunologic fortification, suggesting treatment can reverse the siphoning of intratumor T cells to primary tumor, enabling redistribution to distant tissues and subsequent protection against metastases.

Reversible protein ubiquitination is a crucial factor in cellular homeostasis, with Ubiquitin-Specific Protease 1 (USP1) serving as a key deubiquitinase involved in DNA damage response (DDR) and repair mechanisms in cancer. While ubiquitin ligases have been extensively studied, research on the reverse process of ubiquitination, particularly the mechanisms involving USP1, remains relatively limited. USP1 is overexpressed in various cancers, influencing tumor initiation and progression by regulating multiple associated proteins. Inhibiting USP1 effectively suppresses tumor proliferation and migration and may help overcome resistance to cisplatin and PARP inhibitors. As a potential synthetic lethal target, USP1 demonstrates significant research potential. This review highlights the biological mechanisms of USP1 in cancer progression, the signaling pathways it regulates, and the latest advancements in USP1 inhibitors, while also analyzing the opportunities and challenges of targeting USP1. By adopting the perspective of "the other side of the coin," this review aims to underscore the crucial yet often overlooked role of the deubiquitinase USP1, contrasting it with the extensively studied ubiquitin ligases, and emphasizing its therapeutic potential in cancer treatment.

Breast cancer remains a leading cause of mortality among women worldwide, with existing therapeutic options often accompanied by significant side effects and a persistent risk of disease recurrence. This highlights the need for novel drug candidates with new mechanisms of action by targeting alternative signaling pathways. While hERG channel is notoriously regarded as an off-target due to drug-induced cardiotoxicity, its therapeutic potential as a drug target remains largely unexplored.

This study investigated the role of hERG in breast cancer progression and its impact on patient survival. The anti-proliferative, anti-migratory, anti-invasive and pro-apoptotic effects of hERG activators were evaluated using the Cell Counting Kit-8, wound healing assay, transwell assay and cell apoptosis assay, respectively. Western blotting, Ca2+ imaging and immunofluorescence assays were employed to study their antitumor mechanisms of actions.

We identified two novel hERG activators, SDUY429 and SDUY436, which effectively inhibited the proliferation and migration of MDA-MB-231 and MCF-7 cells. In addition, SDUY436 demonstrated significant anti-invasive and pro-apoptotic effects in MDA-MB-231 cells. Mechanistically, the anti-proliferative activity of hERG activators were mediated through calcineurin activation via enhanced calcium ion influx, which facilitated the nuclear translocation of nuclear factor of activated T cells (NFAT) and upregulated p21Waf/Cip expression. Furthermore, both SDUY429 and SDUY436 remarkably suppressed the migration and invasion of MDA-MB-231 cells by downregulating the protein kinase B (AKT)/glycogen synthase kinase-3 beta (GSK3β)/β-catenin signaling pathway. The observed reduction in phospho-AKT-Ser473 (pAKTS473) expression resulted in the decreased levels of phospho-GSK3β-Ser9 (pGSK3βS9), thereby limiting the nuclear localization of β-catenin, which led to the inhibition of cell migration and invasion. Notably, combining SDUY429 or SDUY436 with the AKT inhibitor MK-2206 produced synergistic anti-proliferative effects.

These findings suggest that hERG activators hold promise as new potential therapeutic agents for the treatment of breast cancer, paving the way for future investigations into their clinical applications.

Calcium (Ca2+) overload therapy gained significant attention in oncology. However, its therapeutic efficacy remained limited due to insufficient Ca2+ accumulation at the tumor site and suboptimal intracellular Ca2+ influx. In this study, gambogic acid (GA), a natural phenolic compound known to promote Ca2+ influx, was encapsulated within an enzyme-triggered, pH-responsive hydrogel (GM@Lip@CHP-Gel) containing Ca2+ hydrogen phosphate nanowires (CHP) to achieve a synergistic approach for bone tumor therapy. GM@Lip@CHP-Gel selectively responded to the slightly acidic tumor microenvironment, triggering degradation of its 3D network structure and sustaining the release of GA and Ca2+ into tumor cells. GA subsequently stimulated Ca2+ influx in tumor cells, effectively disrupting Ca2+ homeostasis. CHP nanowires served as a continuous Ca2+ source, enhancing GA-mediated Ca2+ overload and promoting mitochondrial apoptosis in tumor cells. The combined strategy resulted in an in vivo tumor suppression rate of 79 % and a lung metastasis inhibition rate of 89.4 %, with a protective effect on bone tissue. The naturally derived, Ca2+-mediated treatment demonstrated physiochemical stability in physiological environments and minimized side effects on healthy organs, positioning it as a promising approach for clinical bone cancer therapy.

Magnetic resonance imaging (MRI) is a noninvasive and radiation-free technique used for soft tissue. However, there are some limitations of the MRI modality, such as low sensitivity and poor image resolution. Artificially engineered magnetic nanoprobes have been extensively explored as a versatile platform for ultrasensitive MRI contrast agents due to their unique physiochemical characteristics and tunable magnetic properties. In this review, the emphasis is on recent progress in MRI nanoprobes with different structures and elements, including gadolinium-, iron-, manganese-based and metal-free nanoprobes. The key influencing factors and advanced engineering strategies for modulating the relaxation ratio of MRI nanoprobes are systematically condensed. Furthermore, the widespread and noninvasive visualization applications of MRI nanoprobes for real time monitoring of major organs and accurate disease diagnosing, such as cerebrovascular, ischemia, Alzheimer's disease, liver fibrosis, whole-body tumors, inflammation, as well as multi-mode imaging applications are summarized. Finally, the challenges and prospects for the future development of MRI nanoprobes are discussed, and promising strategies are specifically emphasized for improving biocompatibility, precisely engineering of optimal size, AI-driven prediction and design, and multifunctional self-assembly to enhance diagnostics. This review will provide new inspiration for artificial engineering and nanotechnology-based molecular probes for medical diagnosis and therapy with ultrasensitive MRI.

Cancer metastasis is responsible for more than 90% of tumor-related deaths. Especially, metastatic breast cancer (MBC) is a common malignancy with a high mortality among women worldwide. It is urgent to develop effective drugs for the treatment of MBC. Herein, biomimetic chemotherapeutic drug-gene nanoparticles (named TPT-ASOVEGF@MM NPs) were constructed for the combination therapy of MBC. First, topotecan hydrochloride (TPT) and vascular endothelial growth factor antisense oligonucleotide (ASOVEGF) were coself-assembled in water through electrostatic interaction to produce chemotherapeutic drug-gene nanoparticles (TPT-ASOVEGF NPs). Then, the nanoparticles were encapsulated within macrophage membranes (MM) to form biomimetic TPT-ASOVEGF@MM NPs with long circulation time in blood and active tumor-targeting ability. TPT-ASOVEGF@MM NPs can be effectively internalized by breast cancer cells and then the nanoparticles collapse to simultaneously release TPT and ASOVEGF. ASOVEGF can inhibit the expression of VEGF, impeding the process of neovascularization and blocking the metastatic pathway of cancer cells. Meanwhile, TPT can bind to the topoisomerase I-DNA complex to prevent DNA repair and replication, and further induce apoptosis of cancer cells. In addition, TPT can also affect hypoxia-inducible factor 1α (HIF-1α) expression and inhibit hypoxia-induced tumor metastasis to achieve synergistic therapy with ASOVEGF. In MBC mouse models, the in vivo inhibition rate of TPT-ASOVEGF@MM NPs for lung metastasis was 89.5%, with minor toxic side effects and the least number of metastatic nodules in the lungs. In summary, TPT-ASOVEGF@MM NPs would be a promising biomimetic nanodrug for chemo-gene combination therapy of MBC with high efficacy and safety in clinics.

Macrophages that acquire an immunosuppressive phenotype play a crucial role in establishing the pre-metastatic niche (PMN), which is essential for facilitating breast cancer metastasis to distant organs. Our study showed that increased activity of the aryl hydrocarbon receptor (AHR) in lung macrophages plays a crucial role in establishing the immunosuppressive PMN in breast cancer. Specifically, AHR activation led to high expression of PD-L1 on macrophages by directly binding to the promoter of Pdl1. This upregulation of PD-L1 promoted the differentiation of regulatory T cells (Tregs) within the PMN, further enhancing immunosuppressive conditions. Mice with Ahr conditional deletion in macrophages had reduced lung metastasis of breast cancer. The elevated AHR levels in PMN macrophages were induced by GM-CSF, which was secreted by breast cancer cells. Mechanistically, the activated STAT5 signaling pathway induced by GM-CSF prevented AHR from being ubiquitinated, thereby sustaining its activity in macrophages. In breast cancer patients, the expression of AHR and PD-L1 was correlated with increased Treg cell infiltration, and higher levels of AHR were associated with a poor prognosis. These findings reveal that the crosstalk of breast cancer cells, lung macrophages, and Treg cells via the GM-CSF-STAT5-AHR-PD-L1 cascade modulates the lung pre-metastatic niche during breast cancer progression.

Breast cancer is the most common cancer and the second leading cause of cancer-related death in women. In advanced stages of the disease, breast cancer can spread and metastasize to the bone, contributing to malignant progression. The roles of tissue stiffness and remodeling of the tumor microenvironment are relevant in influencing cancer progression and invasiveness, but they are still poorly understood. In this study, we aimed to investigate the effect of bone tissue stiffness on breast cancer cell behavior, using 3D cell-biomaterial systems to model the in vivo conditions. For this purpose, we developed a 3D-printable cell array, which is a tunable and reproducible platform on small scale, where each compartment could mimic the physiological cancer environment with a shape and rigidity close to bone tissue. In this system, we observed that in the highly metastatic breast cancer line MDA-MB-231, embedded in PEG-silk fibroin (PSF) hydrogel spheres in the array's cavities, increasing stiffness promotes trans-differentiation into osteoblast-like cells and the production of breast microcalcifications. Moreover, we also tested this 3D model as a platform to evaluate the cell response to the therapy, in particular, investigating the drug sensitivity of the cancer cells to chemotherapeutics, observing a decrease in drug resistance over time in the array.

Breast cancer is one of the deadliest malignancies in women worldwide. Zinc finger protein 32 (ZNF32) has been reported to be involved in autophagy and stem cell like properties of breast cancer cells. However, the effects, mechanisms, target genes and pathways of ZNF32 in breast cancer development have not been fully explored. In this study, stable ZNF32 overexpression breast cancer cell line was generated, and we used RNA-seq and RT-qPCR to quantify and verify the changes in transcription levels in breast cancer cells under ZNF32 overexpression. Transcriptome analysis showed that high expression of ZNF32 is accompanied by changes in downstream focal adhesion, ECM-receptor interaction, PI3K-AKT, HIPPO and TNF signaling pathways, which are critical for the occurrence and development of cancer. Multiple differentially expressed genes (DEGs) were significantly involved in cell proliferation, adhesion and migration, including 11 DEGs such as CA9, CRLF1 and ENPP2P with fundamental change of regulation modes. All the 11 DEGs were validated by RT-qPCR, and 9 of them contained potential transcriptional binding sequences of ZNF32 in their promoter region. This study provides a holistic perspective on the role and molecular mechanism of ZNF32 in breast cancer progression.

Breast cancer remains the leading cause of cancer-related death in women, with 5-year survival rates of as high as 90% for patients with early-stage breast cancer without metastasis, falling to 10% once bone metastases (BM) occur. Currently, there is no cure for breast cancer with BM. However, appropriate treatment can extend survival and improve patients' quality of life. Therefore, it is important to accurately evaluate the presence of BM in patients with breast cancer. The present meta-analysis evaluated the diagnostic performance of 18F-FDG and 18F-NaF as PET/CT tracers for breast cancer-associated BM. The present study aimed to compare the diagnostic performance of fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomographs (PET/CT) and 18F-sodium fluoride (18F-NaF) PET/CT in patients with breast cancer and BM. The PubMed and Embase databases were searched for English literature on the diagnostic performance of 18F-FDG PET/CT and 18F-NaF PET/CT for breast cancer BM, and two authors independently extracted data. All included studies presented data that could be used to construct a 2×2 contingency table. The methodological quality of the selected studies was assessed using QUADAS-2, and forest plots were generated based on the sensitivity and specificity of 18F-FDG PET/CT and 18F-NaF PET/CT in the diagnosis of BM associated with breast cancer. A total of 14 articles were identified, including eight on the analysis of 18F-FDG PET/CT, five on 18F-NaF PET/CT and one on both. The studies on 18F-FDG PET/CT and 18F-NaF PET/CT included 530 and 270 patients, respectively. The pooled sensitivities were 0.88 [95% confidence interval (95% CI), 0.76-0.94] for 18F-FDG PET/CT and 0.98 (95% CI, 0.92-1.00) for 18F-NaF PET/CT, and the pooled specificities were 0.99 (95% CI, 0.97-1.00) and 0.91 (95% CI: 0.76-0.97), respectively. The area under the summary receiver operating characteristic curve for both 18F-FDG PET/CT and 18F-NaF PET/CT was 0.99 (95% CI, 0.98-1.00). Lesion-based analysis using 18F-FDG PET/CT was performed for 909 lesions, with a sensitivity of 0.84 (95% CI, 0.67-1.00) and specificity of 1.00 (95% CI, 0.98-1.00). Compared with 18F-FDG PET/CT, 18F-NaF PET/CT showed higher sensitivity (98 vs. 88%) but lower specificity (91 vs. 99%), although the difference between methods was not statistically significant. In conclusion, the results of the present study indicated that 18F-NaF PET/CT and 18F-FDG PET/CT are both accurate methods for the detection of BM in patients with breast cancer, and have comparable diagnostic accuracy.

Invasive lobular breast cancer (ILBC) is a common cause of breast cancer. Prognosis is dependent on many factors such as metastasis location and hormone receptor positivity. A 59-year-old postmenopausal African-American female who was referred to our clinic in May of 2022 presented with a suspicious small bowel lesion seen on surveillance imaging. The patient was diagnosed 15 years prior, with hormone receptor triple positive ILBC of the left breast, T1N2M0. In March of 2021, the patient was admitted to the hospital for rectal bleeding and was also found to have an elevated carcinoembryonic antigen (CEA) level. Computed tomography of the abdomen and pelvis was performed, which revealed a 4 cm segment of proximal ileum that was indeterminate for inflammation, neoplasm, or focal ischemia. The patient ultimately agreed to proceed with a diagnostic laparoscopy to further identify this area and underwent a small bowel resection. The final pathology of this specimen revealed a poorly differentiated, diffuse-type carcinoma with a focal mucinous matrix. The tumor involved the submucosa, serosa, and pericolonic adipose tissue. The morphology was consistent with metastatic carcinoma originating from ILBC. The hormone receptors for this specimen revealed estrogen-receptor (ER) negative, progesterone-receptor (PR) negative, and human epidermal growth factor receptor-2 (HER-2) negative. Lobular breast cancer metastasis to the small bowel as well as triple positive to triple negative conversion is exceedingly rare. The recurrence and metastasis of breast cancer are considerably high and the survival rate for these individuals has shown little improvement throughout the last decade. Defining relevant prognostic markers is crucial for improved management with known metastasis and triple negative receptors.

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 (Ki) 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.

Breast cancer appears as the major cause of cancer-related deaths in women, with more than 2 260 000 cases reported worldwide in 2020, resulting in 684 996 deaths. Triple-negative breast cancer (TNBC), characterized by the absence of estrogen, progesterone, and human epidermal growth factor type 2 receptors, represents ≈20% of all breast cancers. TNBC has a highly aggressive clinical course and is more prevalent in younger women. The standard therapy for advanced TNBC is chemotherapy, but responses are often short-lived, with high rate of relapse. The lack of therapeutic targets and the limited therapeutic options confer to individuals suffering from TNBC the poorest prognosis among breast cancer patients, remaining a major clinical challenge. In recent years, advances in cancer nanomedicine provided innovative therapeutic options, as nanoformulations play an important role in overcoming the shortcomings left by conventional therapies: payload degradation and its low solubility, stability, and circulating half-life, and difficulties regarding biodistribution due to physiological and biological barriers. In this integrative review, the recent advances in the nanomedicine field for TNBC treatment, including the novel nanoparticle-, exosome-, and hybrid-based therapeutic formulations are summarized and their drawbacks and challenges are discussed for future clinical applications.

Epigenetic deregulation is strongly associated with tumor progression. The identification of natural tumor suppressors to overcome cancer metastasis is urgent for cancer therapy. We investigate whether myeloid/lymphoid or mixed-lineage leukemia translocated (MLLT) family members contribute to breast cancer progression and found that high MLLT6 expression predicted a better prognosis and that gradually decreased MLLT6 expression was accompanied by breast cancer malignancy. MLLT6 was downregulated by hypoxia-induced enrichment of DNMT1 at the MLLT6 promoter. The results of in vitro functional experiments indicated that MLLT6 depletion promoted colony formation and cell migration, probably by hampering apoptosis. RNA profiling revealed that the apoptotic pathway was downregulated following stable knockdown of MLLT6. DNA damage-inducible transcript 3/4 (DDIT3/4) were among the top 10 downregulated genes and may have expression patterns similar to that of MLLT6. Restoring DDIT3/4 expression in cells with MLLT6 depletion blocked colony formation and cell migration and attenuated the successful colonization of breast cancer cells in vivo. We also determined that the transcription factor activating transcription factor 2 is a binding partner of MLLT6 and participates in the MLLT6/ATF2 axis, which was reinforced by inhibition of AKT signaling, in turn inducing DDIT3/4 expression by establishing an active chromatin structure at the DDIT3/4 gene promoters. As MLLT6 promotes breast cancer cell apoptosis by inducing DDIT3/4 expression during metastasis, it could be a novel tumor suppressor. Implications: Control of MLLT6 expression via inhibition of PI3K/AKT kinase activity is a potential therapeutic approach for the management of metastatic breast cancer.

In this study, exhaled breath testing has been considered a promising method for the detection and monitoring of breast cancer (BC).

A high-pressure photon ionization time-of-flight mass spectrometry (HPPI-TOFMS) platform was used to detect volatile organic compounds (VOCs) in breath samples. Then, machine learning (ML) models were constructed on VOCs for the diagnosis of BC and its progression monitoring. Ultimately, 1981 women with useable breath samples were included in the study, of whom 937 (47.3 %) had been diagnosed with BC. VOC panels were used for ML model construction for BC detection and progression monitoring.

On the blinded testing cohort, this VOC-based model successfully differentiated patients with and without BC with sensitivity, specificity, and area under receiver operator characteristic curve (AUC) values of 85.9 %, 90.4 %, and 0.946. The corresponding AUC values when differentiating between patients with and without lymph node metastasis (LNM) or between patients with tumor-node-metastasis (TNM) stage 0/I/II or III/IV disease were 0.840 and 0.708, respectively. While developed VOC-based models exhibited poor performance when attempting to differentiate between patients based on pathological patterns (Ductal carcinoma in situ (DCIS) vs Invasive BC (IBC)) or molecular subtypes (Luminal vs Human epidermal growth factor receptor 2 (HER2+) vs Triple-negative BC (TNBC)) of BC.

Collectively, the HPPI-TOFMS-based breathomics approaches may offer value for the detection and progression monitoring of BC. Additional research is necessary to explore the fundamental mechanisms of the identified VOCs.

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.

A definitive understanding of the interplay between protein binding/migration and membrane curvature evolution is emerging but needs further study. The mechanisms defining such phenomena are critical to intracellular transport and trafficking of proteins. Among trafficking modalities, exosomes have drawn attention in cancer research as these nano-sized naturally occurring vehicles are implicated in intercellular communication in the tumor microenvironment, suppressing anti-tumor immunity and preparing the metastatic niche for progression. A significant question in the field is how the release and composition of tumor exosomes are regulated. In this perspective article, we explore how physical factors such as geometry and tissue mechanics regulate cell cortical tension to influence exosome production by co-opting the biophysics as well as the signaling dynamics of intracellular trafficking pathways and how these exosomes contribute to the suppression of anti-tumor immunity and promote metastasis. We describe a multiscale modeling approach whose impact goes beyond the fundamental investigation of specific cellular processes toward actual clinical translation. Exosomal mechanisms are critical to developing and approving liquid biopsy technologies, poised to transform future non-invasive, longitudinal profiling of evolving tumors and resistance to cancer therapies to bring us one step closer to the promise of personalized medicine.

The migration of breast cancer cells is the main cause of death and significantly regulated by physical factors of the extracellular matrix (ECM). To be specific, the curvature and stiffness of the ECM were discovered to effectively guide cell migration in velocity and direction. However, it is not clear what the extent of effect is when these dual-physical factors regulate cell migration. Moreover, the mechanobiology mechanism of breast cancer cell migration in the molecular level and analysis of cell traction force (CTF) are also important, but there is a lack of systematic investigation. Therefore, we employed a microfluidic platform to construct hydrogel microspheres with an independently adjustable curvature and stiffness as a three-dimensional substrate for breast cancer cell migration. We found that the cell migration velocity was negatively correlated to curvature and positively correlated to stiffness. In addition, curvature was investigated to influence the focal adhesion expression as well as the assignment of F-actin at the molecular level. Further, with the help of a motor-clutch mathematical model and hydrogel microsphere stress sensors, it was concluded that cells perceived physical factors (curvature and stiffness) to cause changes in CTF, which ultimately regulated cell motility. In summary, we employed a theoretical model (motor-clutch) and experimental strategy (stress sensors) to understand the mechanism of curvature and stiffness regulating breast cancer cell motility. These results provide evidence of force driven cancer cell migration by ECM physical factors and explain the mechanism from the perspective of mechanobiology.

Chronic stress-induced epinephrine (EPI) accelerates breast cancer progression and metastasis, but the molecular mechanisms remain unclear. Herein, we found a strong positive correlation between circulating EPI levels and the tumoral expression of ubiquitin-specific peptidase 22 (USP22) in patients with breast cancer. USP22 facilitated EPI-induced breast cancer progression and metastasis by enhancing adipose triglyceride lipase (ATGL)-mediated lipolysis. Targeted USP22 deletion decreased ATGL expression and lipolysis, subsequently inhibiting EPI-mediated breast cancer lung metastasis. USP22 acts as a bona fide deubiquitinase for the Atgl gene transcription factor FOXO1, and EPI architects a lipolysis signaling pathway to stabilize USP22 through AKT-mediated phosphorylation. Notably, USP22 phosphorylation levels are positively associated with EPI and with downstream pathways involving both FOXO1 and ATGL in breast cancers. Pharmacological USP22 inhibition synergized with β-blockers in treating preclinical xenograft breast cancer models. This study reveals a molecular pathway behind EPI's tumor-promoting effects and provides a strong rationale for combining USP22 inhibition with β-blockers to treat aggressive breast cancer.