Jianpi-Tiaoqi decoction inhibits tumour proliferation and lung metastasis in tumour-bearing mice with triple-negative breast cancer.

Traditional Chinese medicine, specifically the Jianpi Tiaoqi (JPTQ) decoction, has been explored for its role in treating breast cancer, particularly in inhibiting lung metastasis in affected mice. Our study evaluated the effects of JPTQ on several factors, including tumour growth, apoptosis, angiogenesis, epithelial-to-mesenchymal transition (EMT) and immune microenvironment regulation. We used bioluminescence imaging to observe in situ tumour growth and potential lung metastasis. Transcriptomic analysis provided insights into gene expression, whereas flow cytometry was used to examine changes in specific immune cells, such as CD4+ T cells and myeloid-derived suppressor cells. Several essential proteins and genes, including vascular endothelial growth factor (VEGF), matrix metalloprotein-9 (MMP-9) and B-cell lymphoma 2 (Bcl-2), were assessed through quantitative real-time polymerase chain reaction, western blotting and immunohistochemistry. Our findings showed that JPTQ treatment inhibited tumour proliferation in cancer-bearing mice. Bioluminescence imaging and pathological analysis indicated a reduction in lung metastasis. Transcriptome analysis of lung and tumour tissues indicated that the genes associated with EMT, angiogenesis, proliferation and apoptosis were regulated in the JPTQ-treated group. Kyoto Encyclopedia of Genes and Genomes analysis suggested enrichment of immune-related pathways. Flow cytometry indicated that JPTQ treatment reduced the proportion of monocyte-myeloid-derived suppressor cells in the lung and increased the number of CD4+ T cells in the peripheral blood and the number of T helper 1 (Th1) cells in the spleen (P < 0.05). E-cadherin and cleaved caspase 3 were upregulated, whereas Snail, Bcl-2, Ki67 and VEGF were downregulated in the lung and tumour tissues; moreover, the expression of MMP-9 was downregulated in the lung tissue (P < 0.05). In essence, JPTQ not only inhibits tumour growth in affected mice, but also promotes positive immune responses, reduces angiogenesis, boosts tumour cell apoptosis, reverses EMT and decreases breast cancer lung metastasis.

Exosomal circSIPA1L3-mediated intercellular communication contributes to glucose metabolic reprogramming and progression of triple negative breast cancer.

BACKGROUND: Breast cancer is the most common malignant tumor, and metastasis remains the major cause of poor prognosis. Glucose metabolic reprogramming is one of the prominent hallmarks in cancer, providing nutrients and energy to support dramatically elevated tumor growth and metastasis. Nevertheless, the potential mechanistic links between glycolysis and breast cancer progression have not been thoroughly elucidated. METHODS: RNA-seq analysis was used to identify glucose metabolism-related circRNAs. The expression of circSIPA1L3 in breast cancer tissues and serum was examined by qRT-PCR, and further assessed its diagnostic value. We also evaluated the prognostic potential of circSIPA1L3 by analyzing a cohort of 238 breast cancer patients. Gain- and loss-of-function experiments, transcriptomic analysis, and molecular biology experiments were conducted to explore the biological function and regulatory mechanism of circSIPA1L3. RESULTS: Using RNA-seq analysis, circSIPA1L3 was identified as the critical mediator responsible for metabolic adaption upon energy stress. Gain- and loss-of-function experiments revealed that circSIPA1L3 exerted a stimulative effect on breast cancer progression and glycolysis, which could also be transported by exosomes and facilitated malignant behaviors among breast cancer cells. Significantly, the elevated lactate secretion caused by circSIPA1L3-mediated glycolysis enhancement promoted the recruitment of tumor associated macrophage and their tumor-promoting roles. Mechanistically, EIF4A3 induced the cyclization and cytoplasmic export of circSIPA1L3, which inhibited ubiquitin-mediated IGF2BP3 degradation through enhancing the UPS7-IGF2BP3 interaction. Furthermore, circSIPA1L3 increased mRNA stability of the lactate export carrier SLC16A1 and the glucose intake enhancer RAB11A through either strengthening their interaction with IGF2BP3 or sponging miR-665, leading to enhanced glycolytic metabolism. Clinically, elevated circSIPA1L3 expression indicated unfavorable prognosis base on the cohort of 238 breast cancer patients. Moreover, circSIPA1L3 was highly expressed in the serum of breast cancer patients and exhibited high diagnostic value for breast cancer patients. CONCLUSIONS: Our study highlights the oncogenic role of circSIPA1L3 through mediating glucose metabolism, which might serve as a promising diagnostic and prognostic biomarker and potential therapeutic target for breast cancer.

Predicting disease recurrence in breast cancer patients using machine learning models with clinical and radiomic characteristics: a retrospective study.

BACKGROUND: The goal is to use three different machine learning models to predict the recurrence of breast cancer across a very heterogeneous sample of patients with varying disease kinds and stages. METHODS: A heterogeneous group of patients with varying cancer kinds and stages, including both triple-negative breast cancer (TNBC) and non-triple-negative breast cancer (non-TNBC), was examined. Three distinct models were created using the following five machine learning techniques: Adaptive Boosting (AdaBoost), Random Under-sampling Boosting (RUSBoost), Extreme Gradient Boosting (XGBoost), support vector machines (SVM), and Logistic Regression. The clinical model used both clinical and pathology data in conjunction with the machine learning algorithms. The machine learning algorithms were combined with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) imaging characteristics in the radiomic model, and the merged model combined the two types of data. Each technique was evaluated using several criteria, including the receiver operating characteristic (ROC) curve, precision, recall, and F1 score. RESULTS: The results suggest that the integration of clinical and radiomic data improves the predictive accuracy in identifying instances of breast cancer recurrence. The XGBoost algorithm is widely recognized as the most effective algorithm in terms of performance. CONCLUSION: The findings presented in this study offer significant contributions to the field of breast cancer research, particularly in relation to the prediction of cancer recurrence. These insights hold great potential for informing future investigations and clinical interventions that seek to enhance the accuracy and effectiveness of recurrence prediction in breast cancer patients.

[Patient with TNBC with early relapse within 12 months from adjuvant treatment.] / Paziente affetta da TNBC con ricaduta precoce entro 12 mesi dal trattamento adiuvante.

Triple negative disease, defined by a lack of tumor cell expression of estrogen receptor, progesterone receptor and HER2, remains to date the worst prognosis subtype and especially in metastatic disease triple negative breast cancer is still un unmet clinical need. However, even in this setting, now we can use new drugs such as immunotherapy and antibodies drug conjugated to improve outcome. Particularly, sacituzumab govitecan is the first Ab drug conjugated demonstrating a significant improvement in terms of overall and progression free survival in patients affected by metastatic TNBC pretreated with 2-3 previous lines of therapy.

[Efficacy of sacituzumab govitecan in a patient with TNBC with early relapse after neoadjuvant chemotherapy.] / Efficacia del sacituzumab govitecan in paziente con TNBC con recidiva precoce dopo chemioterapia neoadiuvante.

Triple-negative breast cancers patients who relapse within 12 months from the end of neoaadjuvant chemotherapy represent a subgroup with a particularly poor prognosis, due to resistance to common chemotherapy treatments. Therefore, innovative therapeutic strategies are necessary for these patients. The therapeutic arsenal for triple-negative breast cancer has been enriched in recent years with new drugs, including antibody-drug conjugates. Sacituzumab govitecan, the first antibody directed against Trop-2, has been shown to improve survival in triple-negative metastatic breast cancer (the most aggressive subtype of breast cancer) in women who have received at least two prior chemotherapy treatments in the metastatic setting. This drug has demonstrated its effectiveness even in patients with early relapse after neoadjuvant treatment. In this clinical case we describe the story of a young patient with triple-negative breast cancer, with lymphnodal recurrence, who relapses within the first 12 months after the end of neoadjuvant chemotherapy. Sacituzumab govitecan resulted in a rapid and impressive clinical and instrumental response, associated with an improvement in quality of life and excellent functional status during therapy.

[Long-term response to second-line treatment with sacituzumab govitecan in a patient affected by brain disease and early relpased TNBC.] / Risposta mantenuta al trattamento di seconda linea con sacituzumab govitecan in paziente con malattia encefalica e sistemica da TNBC.

The higher frequency of metastasization and poor prognosis of triple-negative breast cancer require suitable expertise in order to set up an appropriate and effective treatment plan for these patients. Our case describes the clinical history of a 63-year-old BRCA1/2 wild-type woman with excellent ECOG performance status and advanced PD-L1 negative breast cancer with brain, nodal and hepatic metastases. When occurred the brain progression within one year from neoadjuvant chemotherapy for a locally advanced tumor, the patient was treated with brain stereotaxis and a systemic platinum-based therapy that was not completed due to poor tolerance. Later instrumental examinations confirmed a new systemic and visceral progression, for which the patient underwent new therapy with sacituzumab govitecan (SG). During this treatment, we observed a reduction of the target liver and nodal lesions. The onset after several months of two very small cortico-subcortical metastases, on which stereotactic radiotherapy was performed, did not lead us to discontinuate the treatment, that was ongoing for another six months, with an excellent control both of brain and systemic disease without any symptoms, until a new disease progression at other sites requiring a therapeutic change. The use of antibody-drug conjugates allowed a significant prolongation of time to progression and overall survival in our clinical scenario characterized by poor prognosis due to early recurrence and brain involvement.

N-phenyl pyrazoline derivative inhibits cell aggressiveness and enhances paclitaxel sensitivity of triple negative breast cancer cells.

Protein kinase dysregulation induces cancer cell aggressiveness leading to rapid tumor progression and poor prognosis in TNBC patients. Many small-molecule kinase inhibitors have been tested in clinical trials to treat TNBC patients. In the previous study, we found that N-phenylpyrazoline small molecule acts as a protein kinase inhibitor in cervical cancer cells. However, there remains unknown about N-phenyl pyrazoline potency as a kinase inhibitor and its anti-cancer activity in TNBC cells. In this study, we investigated the activity of N-phenyl pyrazoline against TNBC cells via tyrosine kinase inhibition. Based on the MTT assay, the IC50 values for the N-phenyl pyrazoline 2, 5, A, B, C, and D against Hs578T were 12.63 µM, 3.95 µM, not available, 18.62 µM, 30.13 µM, and 26.79 µM, respectively. While only P5 exhibited the IC50 against MDA MB 231 (21.55 µM). Further, N-phenyl pyrazoline 5 treatment significantly inhibited the cell proliferation rate of Hs578T and MDA MB 231 cells. The migration assay showed that treatment with the compound N-phenyl pyrazoline 5 with 4 µM concentration significantly reduced cell migration of Hs578T cells. N-phenyl pyrazoline 5 treatment at 1 µM and 2 µM was able to reduce the tumorsphere size of Hs578t cells. A combination treatment of P5 and paclitaxel showed a synergistic effect with a combination index score > 1 in both TNBC cells. Further, the P5 predictively targeted the protein kinases that significantly correlated to breast cancer prognosis. The GSEA analysis result shows that receptor tyrosine kinase, Notch3, Notch4, and Ephrin signaling pathways were targeted by P5. The P5 treatment reduced the EGFR expression level and activation in TNBC cells.

Study on the mechanism of heterogeneous tumor-associated macrophages in three subtypes of breast cancer through the integration of single-cell RNA sequencing and in vitro experiments.

BACKGROUND: Tumor-associated macrophages (TAM) exert a significant influence on the progression and heterogeneity of various subtypes of breast cancer (BRCA). However, the roles of heterogeneous TAM within BRCA subtypes remain unclear. Therefore, this study sought to elucidate the role of TAM across the following three BRCA subtypes: triple-negative breast cancer, luminal, and HER2. MATERIALS AND METHODS: This investigation aimed to delineate the variations in marker genes, drug sensitivity, and cellular communication among TAM across the three BRCA subtypes. We identified specific ligand-receptor (L-R) pairs and downstream mechanisms regulated by VEGFA-VEGFR1, SPP1-CD44, and SPP1-ITGB1 L-R pairs. Experimental verification of these pairs was conducted by co-culturing macrophages with three subtypes of BRCA cells. RESULTS: Our findings reveal the heterogeneity of macrophages within the three BRCA subtypes, evidenced by variations in marker gene expression, composition, and functional characteristics. Notably, heterogeneous TAM were found to promote invasive migration and epithelial-mesenchymal transition (EMT) in MDA-MB-231, MCF-7, and SKBR3 cells, activating NF-κB pathway via P38 MAPK, TGF-ß1, and AKT, respectively, through distinct VEGFA-VEGFR1, SPP1-CD44, and SPP1-ITGB1 L-R pairs. Inhibition of these specific L-R pairs effectively reversed EMT, migration, and invasion of each cancer cells. Furthermore, we observed a correlation between ligand gene expression and TAM sensitivity to anticancer drugs, suggesting a potential strategy for optimizing personalized treatment guidance. CONCLUSION: Our study highlights the capacity of heterogeneous TAM to modulate biological functions via distinct pathways mediated by specific L-R pairs within diverse BRCA subtypes. This study might provide insights into precision immunotherapy of different subtypes of BRCA.

Development and validation of peritumoral vascular and intratumoral radiomics to predict pathologic complete responses to neoadjuvant chemotherapy in patients with triple-negative breast cancer.

BACKGROUND: To develop and validate a peritumoral vascular and intratumoral radiomics model to improve pretreatment predictions for pathologic complete responses (pCRs) to neoadjuvant chemoradiotherapy (NAC) in patients with triple-negative breast cancer (TNBC). METHODS: A total of 282 TNBC patients (93 in the primary cohort, 113 in the validation cohort, and 76 in The Cancer Imaging Archive [TCIA] cohort) were retrospectively included. The peritumoral vasculature on the maximum intensity projection (MIP) from pretreatment DCE-MRI was segmented by a Hessian matrix-based filter and then edited by a radiologist. Radiomics features were extracted from the tumor and peritumoral vasculature of the MIP images. The LASSO method was used for feature selection, and the k-nearest neighbor (k-NN) classifier was trained and validated to build a predictive model. The diagnostic performance was assessed using the ROC analysis. RESULTS: One hundred of the 282 patient (35.5%) with TNBC achieved pCRs after NAC. In predicting pCRs, the combined peritumoral vascular and intratumoral model (fusion model) yields a maximum AUC of 0.82 (95% confidence interval [CI]: 0.75, 0.88) in the primary cohort, a maximum AUC of 0.67 (95% CI: 0.57, 0.76) in the internal validation cohort, and a maximum AUC of 0.65 (95% CI: 0.52, 0.78) in TCIA cohort. The fusion model showed improved performance over the intratumoral model and the peritumoral vascular model, but not significantly (p > 0.05). CONCLUSION: This study suggested that combined peritumoral vascular and intratumoral radiomics model could provide a non-invasive tool to enable prediction of pCR in TNBC patients treated with NAC.

The potential mechanism of HIF-1α and CD147 in the development of triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is a subtype of breast cancer with a poor prognosis, and the outcomes of common therapy were not favorable. METHODS: The samples of 84 patients with TNBC and 40 patients with breast fibroadenoma were collected in the pathology department specimen library of our hospital. The prognosis of patients was obtained through outpatient follow-up information, telephone and WeChat contacts, and medical records. The mRNA expression was analyzed using bioinformation and quantitative real-time polymerase chain reaction (qPCR). The protein expression was determined by hematoxylin-eosin staining and immunohistochemical staining. The results of survival analysis were visualized using Kaplan-Meier curves. RESULTS: The immunohistochemical staining showed that hypoxia-inducible factor-1alpha (HIF-1α) was mainly distributed in the nucleus and cytoplasm, while CD147 is mainly distributed in cell membrane and cytoplasm. The qPCR results exhibited that the expression level of HIF-1α and CD147 in TNBC tissue was significantly higher than that in breast fibroadenoma tissue. The expression of HIF-1α was related to the histological grade and lymph node metastasis in TNBC, and the expression of CD147 was related to Ki-67, histological grade and lymph node metastasis. There was a positive relationship between the expression of CD147 and HIF-1α. The upregulated expression of CD147 was closely related to the poor prognosis of OS in TNBC. CONCLUSION: CD147 could be a biomarker for the prognosis of TNBC and closely related to the expression of HIF-1α.

Genome-wide in vivo CRISPR screen identifies TGFß3 as actionable biomarker of palbociclib resistance in triple negative breast cancer.

Triple negative breast cancer (TNBC) remains exceptionally challenging to treat. While CDK4/6 inhibitors have revolutionized HR + breast cancer therapy, there is limited understanding of their efficacy in TNBC and meaningful predictors of response and resistance to these drugs remain scarce. We conducted an in vivo genome-wide CRISPR screen using palbociclib as a selection pressure in TNBC. Hits were prioritized using microarray data from a large panel of breast cancer cell lines to identify top palbociclib sensitizers. Our study defines TGFß3 as an actionable determinant of palbociclib sensitivity that potentiates its anti-tumor effects. Mechanistically, we show that chronic palbociclib exposure depletes p21 levels, contributing to acquired resistance, and that TGFß3 treatment can overcome this. This study defines TGFß3 as an actionable biomarker that can be used to improve patient stratification for palbociclib treatment and exploits the synergistic interaction between CDK4/6 and TGFß3 to propose a new combinatorial treatment for TNBC.

Comparison of the efficacy of taxanes with carboplatin and anthracyclines with taxanes in neoadjuvant chemotherapy for stage II-III triple negative breast cancer: a retrospective analysis.

PURPOSE: The neoadjuvant chemotherapy (NACT) regimen for triple negative breast cancer (TNBC) primarily consists of anthracyclines and taxanes, and the addition of platinum-based drugs can further enhance the efficacy. However, it is also accompanied by more adverse events, and considering the potential severe and irreversible toxicity of anthracyclines, an increasing number of studies are exploring nonanthracycline regimens that combine taxanes and platinum-based drugs. METHODS: The retrospective study included 273 stage II-III TNBC patients who received NACT. The AT group, consisting of 195 (71.4%) patients, received a combination of anthracyclines and taxanes, while the TCb group, consisting of 78 (28.6%) patients, received a combination of taxanes and carboplatin. Logistic regression analysis was performed to evaluate the factors influencing pathological complete response (pCR) and residual cancer burden (RCB). The log-rank test was used to assess the differences in event-free survival (EFS) and overall survival (OS) among the different treatment groups. Cox regression analysis was conducted to evaluate the factors influencing EFS and OS. RESULTS: After NACT and surgery, the TCb group had a higher rate of pCR at 44.9%, as compared to the AT group at 31.3%. The difference between the two groups was 13.6% (OR = 0.559, 95% CI 0.326-0.959, P = 0.035). The TCb group had a 57.7% rate of RCB 0-1, which was higher than the AT group's rate of 42.6%. The difference between the two groups was 15.1% (OR = 0.543, 95% CI 0.319-0.925, P = 0.024), With a median follow-up time of 40 months, the TCb group had better EFS (log-rank, P = 0.014) and OS (log-rank, P = 0.040) as compared to the AT group. Clinical TNM stage and RCB grade were identified as independent factors influencing EFS and OS, while treatment group was identified as an independent factor influencing EFS, with a close-to-significant impact on OS. CONCLUSION: In stage II-III triple TNBC patients, the NACT regimen combining taxanes and carboplatin yields higher rates of pCR and significant improvements in EFS and OS as compared to the regimen combining anthracyclines and taxanes.

Pre-treatment peripheral blood immunophenotyping and response to neoadjuvant chemotherapy in operable breast cancer.

BACKGROUND: Tumor immune infiltration and peripheral blood immune signatures have prognostic and predictive value in breast cancer. Whether distinct peripheral blood immune phenotypes are associated with response to neoadjuvant chemotherapy (NAC) remains understudied. METHODS: Peripheral blood mononuclear cells from 126 breast cancer patients enrolled in a prospective clinical trial (NCT02022202) were analyzed using Cytometry by time-of-flight with a panel of 29 immune cell surface protein markers. Kruskal-Wallis tests or Wilcoxon rank-sum tests were used to evaluate differences in immune cell subpopulations according to breast cancer subtype and response to NAC. RESULTS: There were 122 evaluable samples: 47 (38.5%) from patients with hormone receptor-positive, 39 (32%) triple-negative (TNBC), and 36 (29.5%) HER2-positive breast cancer. The relative abundances of pre-treatment peripheral blood T, B, myeloid, NK, and unclassified cells did not differ according to breast cancer subtype. In TNBC, higher pre-treatment myeloid cells were associated with lower pathologic complete response (pCR) rates. In hormone receptor-positive breast cancer, lower pre-treatment CD8 + naïve and CD4 + effector memory cells re-expressing CD45RA (TEMRA) T cells were associated with more extensive residual disease after NAC. In HER2 + breast cancer, the peripheral blood immune phenotype did not differ according to NAC response. CONCLUSIONS: Pre-treatment peripheral blood immune cell populations (myeloid in TNBC; CD8 + naïve T cells and CD4 + TEMRA cells in luminal breast cancer) were associated with response to NAC in early-stage TNBC and hormone receptor-positive breast cancers, but not in HER2 + breast cancer. TRIAL REGISTRATION: NCT02022202 . Registered 20 December 2013.

Navel orange peel essential oil inhibits the growth and progression of triple negative breast cancer.

BACKGROUND: Triple Negative Breast Cancer (TNBC) is a particular type of breast cancer with the highest mortality rate. Essential oils are concerned more and more as potential anti-cancer drugs. METHODS: TNBC cells were treated with different concentrations of navel orange peel essential oil (NOPEO), and then a variety of  experiments were performed to investigate the changes in the growth and progression of TNBC cells. MTT assay was performed to detect the proliferation of TNBC cells. The changes of cell cycle and apoptosis were analyzed by FACS. In order to explored the migration of TNBC cells, scratch wound assay was carried out. Western blotting and qPCR were used to examine the expression of proteins and mRNA of related genes. Furthermore, RNA-seq was used to analyze the altered genes and explored the possible signal pathway. RESULTS: NOPEO demonstrated dose- and time-dependent suppression of TNBC cell growth. TNBC cells showed an increased percentage of G2/M-phase cells and the protein levels of CyclinB1 and CyclinD1 were decreased after NOPEO treatment. The apoptotic cells were increased in the NOPEO treated TNBC cells. The migration mobility was significantly inhibited by NOPEO. In total, 1376 genes were found to be up-regulated and 1335 genes were down-regulated after NOPEO treatment. According to KEGG and GO pathways, the differentially expressed genes were related to MAPK, Jak/stat and FoxQ signaling pathways. CONCLUSION: This investigation explored the bio-activity and molecular mechanisms of NOPEO against TNBC cells. These results indicated that NOPEO could suppress TNBC growth and migration perhaps via the MAPK and Jak/stat signaling pathways, which may provide theoretical reference for anticancer drug development. NOPEO may be a potential natural product for the chemotherapeutic of TNBC.

Green synthesis of zinc oxide nanoparticles using Rhus coriaria extract and their anticancer activity against triple-negative breast cancer cells.

The growing interest in using plant extracts for the biogenic synthesis of zinc oxide nanoparticles (ZnO NPs) stems from their facile, eco-friendly, and biologically safe approach instead of chemical routes. For the first time, ZnO NPs were successfully biosynthesized using Rhus coriaria fruit aqueous extract as a reducing and capping agent. Characterization revealed that the biosynthesized ZnO NPs possessed a maximum absorbance of approximately 359 nm and closely resembled the hexagonal ZnO wurtzite crystalline structure, with an average crystalline size of 16.69 nm. The transmission electron microscope (TEM) showed the presence of spherical and hexagonal morphologies, with an average grain size of 20.51 ± 3.90 nm. Moreover, the elemental composition of the synthesized ZnO NPs was assessed via energy-dispersive X-ray spectrometry (EDX), and the presence of phytocompounds on their surface was subsequently verified through FT-IR analysis. The ζ-potential of ZnO NPs was recorded at - 19.9 ± 0.1663 mV. Regarding anti-cancer properties, ZnO NPs were found to possess potent anti-tumor effects on MCF-7 and MDA-MB-231 breast cancer cells. Their efficacy was dose-dependent, with IC50 values ranging from 35.04-44.86 µg/mL for MCF-7 and 55.54-63.71 µg/mL for MDA-MB-231 cells. Mechanistic studies in MDA-MB-231 cells revealed apoptosis induction, validated by DAPI staining, confocal microscopy, and Annexin V/PI staining, showing apoptosis by 12.59% and 81.57% at ½ IC50 and IC50 values, respectively. Additionally, ZnO NPs were observed to provoke S-phase arrest and inhibit colony-forming and metastatic potential by modulating apoptosis and metastasis-related genes. This study unravels new insights into how ZnO NPs provoke cancer cell death and inhibit metastasis, revealing new prospects in cancer nanotechnology.

Ultrasound-based comparative analysis and nomogram development for predicting triple-negative and non-triple-negative breast cancer: a 4-year institutional study in Quanzhou First Hospital.

OBJECTIVE: The objective of this study was to compare ultrasound features and establish a predictive nomogram for distinguishing between triple-negative breast cancer (TNBC) and non-TNBC. DESIGN: A retrospective cohort study. SETTING: This study was conducted at Quanzhou First Hospital, a grade A tertiary hospital in Quanzhou, China, with the research data set covering the period from September 2019 to August 2023. PARTICIPANTS: The study included a total of 205 female patients with confirmed TNBC and 574 female patients with non-TNBC, who were randomly divided into a training set and a validation set at a ratio of 7:3. MAIN OUTCOME MEASURES: All patients underwent ultrasound examination and received a confirmatory pathological diagnosis. Nodules were classified according to the Breast Imaging-Reporting and Data System standard. Subsequently, the study conducted a comparative analysis of clinical characteristics and ultrasonic features. RESULTS: A statistically significant difference was observed in multiple clinical and ultrasonic features between TNBC and non-TNBC. Specifically, in the logistic regression analysis conducted on the training set, indicators such as posterior echo, lesion size, presence of clinical symptoms, margin characteristics, internal blood flow signals, halo and microcalcification were found to be statistically significant (p<0.05). These significant indicators were then effectively incorporated into a static and dynamic nomogram model, demonstrating high predictive performance in distinguishing TNBC from non-TNBC. CONCLUSION: The results of our study demonstrated that ultrasound features can be valuable in distinguishing between TNBC and non-TNBC. The presence of posterior echo, size, clinical symptoms, margin, internal flow, halo and microcalcification was identified as predictive factors for this differentiation. Microcalcification, hyperechoic halo, internal flow and clinical symptoms emerged as the strongest predictive factors, indicating their potential as reliable indicators for identifying TNBC and non-TNBC.

HUNK as a key regulator of tumor-associated macrophages in triple negative breast cancer.

Triple-negative breast cancer (TNBC) lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC tumors are not sensitive to endocrine therapy, and standardized TNBC treatment regimens are lacking. TNBC is a more immunogenic subtype of breast cancer, making it more responsive to immunotherapy intervention. Tumor-associated macrophages (TAMs) constitute one of the most abundant immune cell populations in TNBC tumors and contribute to cancer metastasis. This study examines the role of the protein kinase HUNK in tumor immunity. Gene expression analysis using NanoString's nCounter PanCancer Immune Profiling panel identified that targeting HUNK is associated with changes in the IL-4/IL-4 R cytokine signaling pathway. Experimental analysis shows that HUNK kinase activity regulates IL-4 production in mammary tumor cells, and this regulation is dependent on STAT3. In addition, HUNK-dependent regulation of IL-4 secreted from tumor cells induces polarization of macrophages into an M2-like phenotype associated with TAMs. In return, IL-4 induces cancer metastasis and macrophages to produce epidermal growth factor. These findings delineate a paracrine signaling exchange between tumor cells and TAMs regulated by HUNK and dependent on IL-4/IL-4 R. This highlights the potential of HUNK as a target for reducing TNBC metastasis through modulation of the TAM population.

Celecoxib Augments Paclitaxel-Induced Immunogenic Cell Death in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly aggressive malignancy that lacks effective targeted therapies. Inducing immunogenic cell death (ICD) in tumor cells represents a promising strategy to enhance therapeutic efficacy by promoting antitumor immunity. Paclitaxel (PTX), a commonly used chemotherapy drug for TNBC, can induce ICD; however, the resulting immunogenicity is limited. Thus, there is an urgent need to explore strategies that improve the effectiveness of ICD in TNBC by incorporating immunoregulatory agents. This study investigated the potential of celecoxib (CXB) to enhance PTX-induced ICD by blocking the biosynthesis of PGE2 in the tumor cells. We observed that the combination of CXB and PTX promoted the maturation of dendritic cells and primed a T cell-dependent immune response, leading to enhanced tumor rejection in a vaccination assay. To further optimize drug delivery in vivo, we developed cRGD-modified liposomes for the targeted codelivery of CXB and PTX. This delivery system significantly improved drug accumulation and triggered robust antitumor immunity in an orthotopic mouse model of TNBC. Moreover, it served as an in situ vaccine to inhibit tumor recurrence and lung metastasis. Overall, our findings provide in-depth insights into the therapeutic mechanism underlying the combination of CXB and PTX, highlighting their potential as effective immune-based therapies for TNBC.

Self-activating chitosan-based nanoparticles for sphingosin-1 phosphate modulator delivery and selective tumor therapy.

This study reports on the design and synthesis of hypoxia responsive nanoparticles (HRNPs) composed of methoxy polyethylene glycol-4,4 dicarboxylic azolinker-chitosan (mPEG-Azo-chitosan) as ideal drug delivery platform for Fingolimod (FTY720, F) delivery to achieve selective and highly enhanced TNBC therapy in vivo. Herein, HRNPs with an average size of 49.86 nm and a zeta potential of +3.22 mV were synthetized, which after PEG shedding can shift into a more positively-charged NPs (+30.3 mV), possessing self-activation ability under hypoxia situation in vitro, 2D and 3D culture. Treatment with lower doses of HRNPs@F significantly reduced MDA-MB-231 microtumor size to 15 %, induced apoptosis by 88 % within 72 h and reduced highly-proliferative 4 T1 tumor weight by 87.66 % vs. ∼30 % for Fingolimod compared to the untreated controls. To the best of our knowledge, this is the first record for development of hypoxia-responsive chitosan-based NPs with desirable physicochemical properties, and selective self-activation potential to generate highly-charged nanosized tumor-penetrating chitosan NPs. This formulation is capable of localized delivery of Fingolimod to the tumor core, minimizing its side effects while boosting its anti-tumor potential for eradication of TNBC solid tumors.

[Tumor infiltrating lymphocytes (TILs) in triple negative breast cancer]. / Infil'triruyushchie opukhol' limfotsity (TILs) pri trizhdy negativnom rake molochnoi zhelezy.

BACKGROUND: Tumor infiltrating lymphocytes (TILs) are a promising inexpensive prognostic and predictive biomarker in breast cancer. High levels of TILs are associated with improved survival and higher probability to achieve pathological complete response in triple-negative breast cancer (TNBC). OBJECTIVE: To assess the level of TILs in TNBC samples and analyze the association between the level of TILs and the main pathological parameters, to identify their impact on long-term results. MATERIAL AND METHODS: The study included information on 140 patients with I-III stage TNBC and estrogen receptors <10%. Tumor tissue samples at baseline biopsies were evaluated the histological type, HER2 expression, estrogen expression levels, Ki-67 and TILs. The pathological response was evaluated according to the ypTNM, Miller-Payne, and RCB classifications. RESULTS: The average level of TILs in biopsy specimens before NACT was 29.3±23.1%. Low levels of TILs (<10%) were defined in 21% of cases, intermediate levels (≥10% to ≤40%) in 55% of cases, and high levels (>40%) in 24% of cases. Using the two-tiered system, low TILs (≤40%) were defined in 76% and high TILs (>40%) in 24% of cases. The level of TILs was correlated with histological grade (R=0.187; p=0.027) and estrogen receptor expression level (R=0.211; p=0.012). There were no significant differences depending on the level of TILs and other pathological parameters. Three-year event-free survival (EFS) in patients with high TILs levels was 95% versus 65% in the low TILs group (p=0.037). CONCLUSION: Stromal TILs are an important prognostic biomarker in TNBC. Using a cutoff of 40%, high TILs are significantly associated with longer EFS.