Triple negative breast cancer, an inherently aggressive disease, is further impaired by the limited therapeutic options and chemotherapy-resistance; hence, elucidating the signaling nodes underlying chemotherapy resistance is of major interest. Focusing on the differentially expressed genes in recurrent TNBC, we identified TRIM29, a ubiquitin ligase belonging to TRIM family, as a uniquely enriched protein in chemoresistant TNBC. Here, we demonstrate that chemoresistant TNBC cells are inherently aggressive, exhibiting elevated growth and migration potential compared to chemosensitive cells, and in particular, they possess higher TRIM29 expression whose expression level modulation results in altered chemosensitivity. TRIM29 overexpression reduces chemotherapy response whereas TRIM29 knockout not only increases chemosensitivity but also reduces TNBC tumor growth. Tumor-dissociated cells maintain TRIM29 knockout status as well as exhibit similar functional alterations as chemoresistant TNBC cells. Mechanistically, RNA-sequencing of parental-chemosensitive, chemoresistant-inherently overexpressing TRIM29 and chemoresistant-TRIM29 knockout TNBC cells reveals a unique set of genes (S100P, SERPINB3, SERPINB4, CEACAM5, CEACAM6 and CDH6) showing significant upregulation with the acquisition of chemoresistance and downregulation with the TRIM29 knockout. Furthermore, an enrichment of β-catenin pathway in chemoresistant TNBC cells is observed. We uncovered a functional network where S100P, a metastasis inducing secretory factor, bidirectionally interacts with TRIM29, and modulates the expression of SERPINB3, SERPINB4, CEACAM5, CEACAM6 as well as β-catenin pathway genes. Showing the functional importance, S100P inhibitor reduces the growth and mammosphere formation in chemoresistant TNBC. Moreover, combining β-catenin inhibitor with chemotherapy shows synergistic inhibition of chemoresistant TNBC cells. Indeed, higher expression of TRIM29, S100P and β-catenin associates with reduced recurrence free survival. This work proposes TRIM29 as an important node that modulates a unique gene network in chemoresistant TNBC and whose biological impact is mediated by modulation of S100P and β-catenin.

NF-κB signalling is frequently dysregulated in human cancers making it an attractive therapeutic target. Despite concerted efforts to generate NF-κB inhibitors, direct pharmacological inhibition of the kinases mediating canonical NF-κB has failed due to on-target toxicities in normal tissues. So, alternative strategies, designed to target specific components of the NF-κB signalling machinery, have the potential to selectively inhibit tumour cells whilst reducing the toxicities associated with broad inhibition of NF-κB in non-malignant cells. Here we present evidence that a C8-linked pyrrolobenzodiazepine (PBD) containing proteolysis-targeting chimera (PROTAC) selectively degrades the NF-κB subunit, RelA/p65, in a proteasome-dependent manner. Our lead PROTAC (JP-163-16, 15d) showed cytotoxicity with mean LC50 values of 2.9 μM in MDA-MB-231 cells, 0.14 μM in MEC-1 cells and 0.23 μM in primary chronic lymphocytic leukaemia cells. In contrast, 15d was two-logs less toxic in primary B- and T-lymphocytes (mean LD50 19.1 μM and 36.4 μM, respectively). Importantly, the development of 15d, by conjugating the C8-linked PBD with a cereblon-targeting ligand using a five-carbon linker, abolished the ability of the C8-linked PBD to bind to DNA, whilst demonstrating cytotoxicity in cancer cells associated with the degradation of RelA/p65. Mechanistically, 15d displayed PROTAC credentials through the selective degradation of NF-κB RelA/p65 in a proteasome-dependent manner and showed a five-fold reduction in potency in the cereblon deficient, lenalidomide resistant, myeloma cell line, RPMI-8226. To our knowledge, this work describes the first PROTAC capable of selective degradation of a single NF-κB subunit and highlights the therapeutic potential of our strategy for the treatment of RelA/p65-dependent tumours.

Sacituzumab govitecan (SG) is approved for the treatment of metastatic triple-negative breast cancer (mTNBC). We report the real-world clinical effectiveness and toxicity data of SG in patients with mTNBC.

A multi-institution retrospective study of patients with mTNBC treated with SG from January 2021 to May 2023 was conducted. Demographic and clinicopathologic variables were collected. Univariate and multivariate Cox regression models were used for survival analysis.

A total of 115 patients were included. The median age at SG initiation was 60 years (range, 31-85). All patients were female; 73 (63.5%) were White and 31 (27.0%) were Black. The median number of previous therapies in the metastatic setting was two (range, 0-8). Sixty-one (56.0%) patients had primary refractory disease. Median relative dose intensity was 92% (range, 33%-100%). Grade 3 or higher adverse events (AEs) were seen in 50.9% of patients, which included neutropenia (35.7%), anemia (27.0%), vomiting (16.5%), fatigue (8.7%), and diarrhea (7.0%). Dose reductions and treatment discontinuation due to AEs were required in 51.3% and 13.2%, respectively. The objective response rate (ORR) was 27.8%. Median overall survival was 9.6 months (95% CI, 7.8 to 12.9) and median progression-free survival (PFS) was 4.8 months (95% CI, 3.6 to 5.9). In patients with human epidermal growth factor receptor 2 (HER2)-low mTNBC who received trastuzumab deruxtecan (T-DXd) after SG, the ORR to T-DXd was 34.8% and median PFS was 7 months (95% CI, 4.6 to 10.1).

In a real-world cohort of heavily pretreated patients with mTNBC, SG retains its clinical activity. In a subgroup with HER2-low disease, T-DXd continues to demonstrate promising clinical activity after SG, supporting the use of sequential antibody-drug conjugates in this population.

Metastatic progression depends upon the ability of disseminated tumor cells to evade immune surveillance. MHC molecule expression facilitates T cell recognition and activation to permit the eradication of metastatic tumor cells. We identified nuclear corepressor 2 (NCOR2) as a key epigenetic regulator of MHC class I molecule expression on breast tumor cells. Patients with triple negative breast cancers (TNBC) that expressed high levels of NCOR2 also exhibited reduced metastasis free survival and decreased MHC class I expression, and the metastatic lesions in patients with TNBC had high nuclear NCOR2 and reduced CD8 T cell levels and activity. Genetically and experimentally reducing NCOR2 expression in tumor cells permitted interferon gamma upregulation of MHC class I, and potentiated CD8 T cell activity and induction of apoptosis to repress metastatic progression of disseminated breast cancer cells. These studies provide evidence to support NCOR2 as a targetable epigenetic regulator of metastasis towards which therapies could be developed to reduce patient mortality.

Triple-negative breast cancer (TNBC) is the breast cancer subtype with the poorest prognosis and lacks actionable molecular targets for treatment. Maternal embryonic leucine zipper kinase (MELK) is highly expressed in TNBC and has been implicated in poor clinical outcomes, though its mechanistic role in the aggressive biology of TNBC is poorly understood. Here, we demonstrate a role of MELK in TNBC progression and metastasis. Analysis of publicly available datasets revealed that high MELK expression correlates with worse overall survival, recurrence-free survival, and distant metastasis-free survival, and MELK is co-expressed with metastasis-related genes. Functional studies demonstrated that MELK inhibition, using genomic or pharmacologic inhibition, reduces mammosphere formation, migration, and invasion in high-MELK-expressing TNBC cell lines. Conversely, MELK overexpression in low-MELK-expressing cell lines significantly increased invasive capacity in vitro and metastatic potential in vivo, as evidenced by enhanced metastasis to the liver and lungs in a chorioallantoic membrane assay. These findings highlight MELK as a key regulator of TNBC aggressiveness and support its potential as a therapeutic target to mitigate metastasis and improve patient outcomes.

Breast cancer is the most common malignancy diagnosed in women worldwide. Triple-negative breast cancer (TNBC) is the most aggressive subtype, accounting for nearly one third of all breast cancers in India. The addition of pembrolizumab to neoadjuvant chemotherapy improved the pathological response and event free survival in patients with TNBC. However, for most patients in low- and middle-income countries, immunotherapy remains inaccessible due to its high cost. Pharmacological and early clinical data suggest that a lower dose of pembrolizumab may be effective. However, there are no prospective clinical trials in patients with TNBC.

This is a single-site phase II, randomized, open-labeled, parallel-group trial. Eligible patients will be randomized (1:1) to either of the two treatment groups. Patients in the control arm will be administered standard of care chemotherapy [4 cycles of dose-dense doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2), followed by 4 cycles of dose-dense paclitaxel (175 mg/m2)]. Patients in the experimental arm will receive 3 doses of pembrolizumab 50 mg every 6 weeks along with neoadjuvant dose-dense chemotherapy. The primary objective of the study is to compare the pathological complete response with the addition of low-dose pembrolizumab to neoadjuvant chemotherapy in patients with TNBC. Secondary objectives include invasive disease-free survival and quality of life assessment.

The PLANeT trial aims to establish the efficacy of low-dose pembrolizumab in addition to neoadjuvant chemotherapy in patients with triple-negative breast cancer patients. This strategy, if found effective, will help improve the outcomes of women with TNBC who currently have limited access to pembrolizumab.

Clinical Trials Registry of India-CTRI/2024/01/062088.

This review evaluates the financial burden of current treatments for triple-negative breast cancer (TNBC) and projects potential financial scenarios to assess the feasibility of introducing a peptide-based neoantigen cancer vaccine (NCV) targeting the disease, using the UK as a healthcare system model. TNBC, the most aggressive breast cancer subtype, is associated with poor prognosis, worsened by the lack of personalised treatment options. Neoantigen cancer vaccine therapies present a personalised alternative with the potential to enhance T-cell responses independently of genetic factors, unlike approved immunotherapies for TNBC. Through a systematic literature review, the underlying science and manufacturing processes of NCVs are explored, the direct medical costs of existing TNBC treatments are enumerated, and two contrasting pricing scenarios for NCV clinical adoption are evaluated. The findings indicate that limited immunogenicity is the main scientific barrier to NCV clinical advancement, alongside production inefficiencies. Financial analysis shows that the UK spends approximately GBP 230 million annually on TNBC treatments, ranging from GBP 2200 to GBP 54,000 per patient. A best-case pricing model involving government-sponsored NCV therapy appears financially viable, while a worst-case, privately funded model exceeds the National Institute for Health and Care Excellence (NICE) cost thresholds. This study concludes that while NCVs show potential clinical benefits for TNBC, uncertainties about their standalone efficacy make their widespread adoption in the UK unlikely without further clinical research.

Breast cancer (BrCa) is a complex and heterogeneous disease with diverse molecular subtypes, leading to varied clinical outcomes and posing significant treatment challenges. The increasing global burden of BrCa, particularly in low- and middle-income countries, underscores the urgent need for more effective therapeutic strategies. The androgen receptor (AR), expressed in a substantial proportion of breast cancer cases, has emerged as a potential biomarker and therapeutic target. In breast cancer, AR exhibits diverse functions across subtypes, often interacting with other hormone receptors, thereby influencing tumor progression and treatment responses. This intricate interplay is further complicated by the presence of constitutively expressed AR splice variants (AR-Vs) that drive resistance to AR-targeting therapies through structural rearrangements in the domains and activation of aberrant signaling pathways. Although AR-targeting drugs, initially developed for prostate cancer (PCa), have shown promise in AR-positive breast cancer, significant gaps remain in understanding AR's precise functions and therapeutic potential. The systemic management of breast cancer is guided primarily by theranostic biomarkers; ER, PR, HER2, and Ki67 which also dictate the breast cancer classification. The ubiquitous expression of AR in BrCa and the emergence of AR-Vs can assist the management of disease complementing the standard of care. This article provides a comprehensive overview of AR and its splice variants in the context of breast cancer, highlighting their prognostic and predictive value across different subtypes looking beyond the conventional ER, PR, and HER2 status. This review also raises the possibility of using AR splice variants in predicting tumor aggressiveness. From the settings of developing nations, this may provide useful insight by integrating recent advances in AR-targeted therapies and exploring their translational potential, emphasizing the critical need for further research to optimize AR-based therapeutic strategies for breast cancer management.

Triple-negative breast cancer (TNBC) is a diverse category with a subset that displays particularly aggressive characteristics, referred to in this study as "rapid relapse" TNBC (rrTNBC). This term is defined as the occurrence of distant metastasis or death within 24 months post-diagnosis. The paper mainly studies the clinicopathologic traits of TNBC patients experiencing rapid disease progression and chemotherapy resistance and identify predictive markers for this outcome. A retrospective evaluation was conducted on 2294 TNBC patients who underwent surgery at Tianjin Medical University Cancer Hospital. Of these, 369 were categorized as experiencing rapid relapse, while 1925 did not relapse rapidly. Logistic regression analysis was applied to determine potential markers predictive of rapid relapse post-chemotherapy. Both univariate and multivariate logistic regression analyses pinpointed several predictors of rapid relapse in TNBC patients post-chemotherapy. These include age at diagnosis (≥ 50 years, OR = 0.413, 95% CI: 0.289-0.590), postoperative pathological T staging (T2, OR = 2.557, 95% CI: 1.766-3.703; T3 + T4, OR = 3.725, 95% CI: 1.355-10.454), and N staging (N1, OR = 3.056, 95% CI: 2.021-4.619; N2, OR = 6.917, 95% CI: 3.920-12.206; N3, OR = 24.597, 95% CI: 11.875-50.948). Additionally, sTIL expression (intermediate, OR = 0.204, 95% CI: 0.139-0.300; high, OR = 0.020, 95% CI: 0.011-0.035) and Her2 expression (Her2 1+, OR = 0.470, 95% CI: 0.321-0.688) were identified as protective indicators against rapid relapse. A predictive model incorporating these predictors yielded a C-index of 0.898 in the training set and 0.938 in the validation set, with respective Brier scores of 0.079 and 0.073. The study successfully established and validated a predictive model for rapid disease progression and chemotherapy resistance in TNBC patients post-chemotherapy, demonstrating robust discrimination and accuracy.

The lack of targeted therapy for triple-negative breast cancer (TNBC) is among the mainsprings of its poor prognosis. This study aimed to elucidate the role of the androgen receptor (AR) and its splice variant 7 (ARv7) in TNBC patients. Further, the molecular impact of their blockers, Enzalutamide and EPI-001, on the TNBC cell line MDA-MB-231 was investigated. Thereby, immunohistochemical expression of AR/ARv7 was assessed for TNBC Egyptian patients. Moreover, bioinformatics analysis of AR/ARv7 RNA status was carried out on TNBC patients from The Cancer Genome Atlas Breast Carcinoma project (TCGA-BRCA). Data from both groups was correlated with patients' clinicopathological features. Besides, scratch wound healing assay and ELISA were employed to assess the effect of AR/ARv7 blockers on several metastasis markers in MDA-MB-231 cell line. In the Egyptian-TNBC patients, AR expression was associated with worse 7-year DFS (40.6 ± 18.6 %). In addition, ARv7 showed cytoplasmic and nuclear patterns, and both cytoplasmic and nuclear ARv7+ patients demonstrated a worse 7-year DFS (22.7 ± 17.7 % and 20 ± 17.9 %) and overall survival (63.6 ± 14.5 % and 40 ± 21.8 %). Importantly, 80 % of the nuclear ARv7+ patients developed distant metastasis. The data of the TCGA-TNBC patients showed a tendency for poor outcomes in the high ARv7-expressing patients. Molecularly, in MDA-MB-231, both inhibitors modulated metastasis and epithelial to mesenchymal transition (EMT) markers ROCK1, ROCK2, c-Myc, E-cadherin and N-cadherin, with EPI-001 downregulating NF-ĸB level as well. We concluded that ARv7 indicated poor prognosis in the studied cohorts and that blocking of AR/ARv7 abated metastasis and key regulators of EMT in MDA-MB-231, at least in part by targeting ROCK/NF-ĸB/c-Myc axis.

Triple-Negative Breast Cancer (TNBC), the most challenging subtype of Breast Cancer (BC), currently lacks targeted therapy, presenting a significant therapeutic gap in its management. Tumor Associated Macrophages (TAMs) play a significant role in TNBC progression and could be targeted by repolarizing them from M2 to M1 phenotype. Matairesinol (MAT), a plant lignan, has been shown to exhibit anticancer, anti-inflammatory and immunomodulatory activities. In this study, we explored how MAT-induced repolarization of THP-1-derived M2 macrophages towards the M1 phenotype, which could effectively target the TNBC cell line, MDA-MB-231.

The differential expression of genes in THP-1-derived macrophages at mRNA levels was evaluated by RNAseq assay. An inverted microscope equipped with a CMOS camera was utilized to capture the morphological variations in THP-1 cells and THP-1-derived macrophages. Relative mRNA expression of M1 and M2 specific marker genes was quantified by qRT-PCR. Cell viability and induction of apoptosis were evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide (JC-1 dye) assays, respectively.

MAT reduced the viability of M2a and M2d macrophages and repolarized them to M1 phenotype. Conditioned medium (CM) from MAT-treated M2a and M2d macrophages significantly reduced the viability of TNBC cells by apoptosis.

Targeting M2 macrophages is an important strategy to regulate cancer progression. Our study provides evidence that MAT may be a promising drug candidate for developing novel anti-TNBC therapy. However, further studies are warranted to thoroughly elucidate the molecular mechanism of action of MAT and evaluate its therapeutic potential in TNBC in vitro and in vivo models.

Triple-negative breast cancer (TNBC) is incurable and prone to widespread metastasis. Therefore, identification of key targets for TNBC progression is urgently needed. Our previous study revealed that isotoosendanin (ITSN) reduced TNBC metastasis by targeting TGFβR1. ITSN is currently used as an effective chemical probe to further discover the key molecules involved in TNBC metastasis downstream of TGFβR1. The results showed that GOT2 was the gene downstream of Smad2/3 and that ITSN decreased GOT2 expression by abrogating the activation of the TGF-β-Smad2/3 signaling pathway through directly binding to TGFβR1. GOT2 was highly expressed in TNBC, and its knockdown decreased TNBC metastasis. However, GOT2 overexpression reversed the inhibitory effect of ITSN on TNBC metastasis both in vitro and in vivo. GOT2 interacted with MYH9 and hindered its binding to the E3 ubiquitin ligase STUB1, thereby reducing MYH9 ubiquitination and degradation. Moreover, GOT2 also enhanced the translocation of MYH9 to mitochondria and thus induced DRP1 phosphorylation, thereby promoting mitochondrial fission and lamellipodia formation in TNBC cells. ITSN-mediated inhibition of mitochondrial fission and lamellipodia formation was associated with reduced GOT2 expression. In conclusion, ITSN prevented MYH9-regulated mitochondrial fission and lamellipodia formation in TNBC cells by enhancing MYH9 protein degradation through a reduction in GOT2 expression, thus contributing to its inhibition of TNBC metastasis.

In this study, the copper(II) complex [Cu(chromoneTSC)Cl2]•0.5H2O•0.0625C2H5OH (where chromoneTSC = (E)-N-Ethyl-2-((4-oxo-4H-chromen-3-yl)methylene)-hydrazinecarbothioamide) was synthesized and characterized; then used to carry out in vitro studies in combination with berberine chloride (BBC). The ligand and complex were characterized by elemental analysis, FTIR and NMR (1H and 13C) spectroscopy, and conductivity measurements. The cytotoxic effect was analyzed by using the CCK-8 viability assay in cancer MDA-MB-231 VIM RFP and non-cancer MCF-10A cell lines. The IC50 values for the complex and BBC were 21.2 ±1.6 and 48.3 ± 2.4 μM, respectively at 24 h incubation, while the IC50 value of the combination treatment was 9.3 ± 1.5 in cancer cells. The co-treatment group significantly increased the number of cells in G2 phase, indicating the growth arrest of cancer cells. Moreover, the combination group showed induction of both intrinsic and extrinsic apoptotic pathways. There was also a study on the effect of the combination treatment on receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and mixed lineage kinase domain-like pseudokinase (MLKL) as biomarkers of necroptosis. The results showed activation of necroptosis after treatment with the combination of the copper complex and BBC via the activation of RIPK3-MLKL pathway.

Cancer metastasis remains a major challenge in the clinical management of triple-negative breast cancer (TNBC). The NF-κB signaling pathway has been implicated as a crucial factor in the development of metastases, but the underlying molecular mechanisms remain largely unclear.

PTPN20 expression was evaluated using data from the Sweden Cancerome Analysis Network-Breast and The Cancer Genome Atlas database, as well as by western blotting and immunohistochemistry in 88 TNBC patients. The ability of PTPN20 to activate NF-κB was assessed by luciferase reporter assays. The effects of PTPN20 overexpression and knockdown via short hairpin RNA were examined in TNBC cell lines by wound healing and transwell matrix penetration assays. Additionally, we analyzed the growth and metastasis abilitiy of 4T1 xenograft tumors in nude mice.

PTPN20 levels were elevated in TNBC cell lines and patient samples compared to controls, and higher protein levels correlated with metastasis-free survival. Overexpression of PTPN20 enhanced migration and invasion in vitro, and promoted lung metastasis in vivo. Our finding revealed that PTPN20 activates NF-κB signaling by dephosphorylating p65 at Ser468, preventing its binding to COMMD1, thereby protecting p65 from degradation. Downregulation of PTPN20 effectively inhibit, while p65 S468A mutant restored the migratory and invasive abilities of TNBC cells.

Collectively, our results demonstrate that PTPN20 plays a critical role in TNBC metastasis through the activation of NF-κB signaling. We propose that PTPN20 may serve as a novel prognostic marker and potential therapeutic target for the treatment of TNBC.

Breast cancer is the most common cancer in women with multiple risk factors including smoking, genetics, environmental factors, and obesity. Smoking and obesity are the top two risk factors for the development of breast cancer. The effect of obesity on adipose tissue mediates the pathogenesis of breast cancer in the context of obesity. Triple-negative breast cancer (TNBC) is a breast cancer subtype within which the cells lack estrogen, progesterone, and HER2 receptors. TNBC is the deadliest breast cancer subtype. The 5-year survival rates for patients with TNBC are 8-16% lower than the 5-year survival rates for patients with estrogen-receptor-positive breast tumors. In addition, TNBC patients have early relapse rates (3-5 years after diagnosis). Obesity is associated with an increased risk for TNBC, larger TNBC tumors, and increased breast cancer metastasis compared with lean women. Thus, novel therapeutic approaches are warranted to treat TNBC in the context of obesity. In this paper, we show that peritumor breast adipose-derived secretome (ADS) from patients with a high (>30) BMI is a stronger inducer of TNBC cell invasiveness and JAG1 expression than peritumor breast ADS from patients with low (<30) BMI. These findings indicate that patient BMI-associated changes in peritumor AT induce changes in peritumor ADS, which in turn acts on TNBC cells to stimulate JAG1 expression and cancer cell invasiveness.

Abnormal expression of connexin 43 (Cx43) contributes to the development and progression of cancer. However, its regulation is complex and dependent on the environment. The expression of Cx43 in triple-negative cancer lesions was analyzed by immunohistochemistry and optical coherence tomography using experimental models and clinical samples. The model of TGFβ1-SMad3-in-αv signal axis was established and verified by experiments. The results show that Cx43 plays a key role in the regulation of triple-negative cancer metastasis. In vivo, over-expressed Cx43 decreased tumor volume and inhibited ITGαV, TGF-β1, Smad3 and N-cadherin expressions, but enhanced the E-cadherin. Cx43 had the lowest expression in the TNBC samples, especially in lymph node metastatic TNBC patients and had a negative correlation with ITG alpha V, TGF-β1 and Smad3.The study demonstrated Cx43 controlled metastatic behavior through TGF-β1 -Smad3-ITG αV signaling axis in MDA-MB-231 cells, providing evidence for Cx43's function in TNBC. The optical image diagnosis method can realize the identification and quantitative evaluation of early cancer triple negative, and provide a new strategy and means for the treatment of cancer triple negative.

Caspase-9, a cysteine-aspartate protease traditionally associated with intrinsic apoptosis, has recently emerged as having non-apoptotic roles, including influencing cell migration-an aspect that has received limited attention in existing studies. In our investigation, we aimed to explore the impact of caspase-9 on the migration and invasion behaviors of MDA-MB-231, a triple-negative breast cancer (TNBC) cell line known for its metastatic properties. We established a stable cell line expressing an inducible caspase-9 (iC9) in MDA-MB-231 and assessed their metastatic behavior using both monolayer and the 3D organotypic model in co-culture with human Foreskin fibroblasts (HFF). Our findings revealed that caspase-9 had an inhibitory effect on migration and invasion in both models. In monolayer culture, caspase-9 effectively suppressed the migration and invasion of MDA-MB-231 cells, comparable to the anti-metastatic agent panitumumab (Pan). Notably, the combination of caspase-9 and Pan exhibited a significant additional effect in reducing metastatic behavior. Interestingly, caspase-9 demonstrated superior efficacy compared to Pan in the organotypic model. Molecular analysis showed down regulation of epithelial-mesenchymal transition and migratory markers, in caspase-9 activated cells. Additionally, flow cytometry analysis indicated a cell cycle arrest. Moreover, pre-treatment with activated caspase-9 sensitized cells to the chemotherapy of doxorubicin, thereby enhancing its effectiveness. In conclusion, the anti-metastatic potential of caspase-9 presents avenues for the development of novel therapeutic approaches for TNBC/metastatic breast cancer. Although more studies need to figure out the exact involving mechanisms behind this behavior.

This study evaluated treatment patterns and clinical outcomes among patients with metastatic triple-negative breast cancer (mTNBC) in real-world clinical settings in Japan.

The treatment patterns, time to next treatment or death (TTNTD), time to treatment discontinuation, adverse events of interest, and medical costs of treating patients with mTNBC in first-, second-, and third-line settings were investigated using data of patients meeting the inclusion criteria between January 2017 and March 2022 in a Japanese medical claims database. The treatment regimens for mTNBC were defined according to the Japanese Breast Cancer Society Clinical Practice Guidelines.

In this study, 2236 patients with mTNBC (median age 66.0 years; 99.8% female) were included in the first-line cohort. Of these, 46.6% and 20.8% were included in the second- and third-line cohorts, respectively. The two most frequently used treatments were capecitabine (19.1%) and S-1 (tegafur-gimeracil-oteracil) (14.5%) in the first-line cohort, eribulin (18.3%) and bevacizumab/paclitaxel (14.4%) in the second-line cohort, and eribulin (19.4%) and bevacizumab/paclitaxel (17.5%) in the third-line cohort. The TTNTD shortened as the line of therapy progressed (median 8.0, 6.5, and 5.2 months for the first-, second-, and third-line treatments, respectively). Nausea/vomiting and neutropenia/leukopenia occurred in 62.8% and 18.3% of all patients, respectively. The medical total costs per day were 6.7, 10.2, and 12.9 thousand yen during the first-/second-/third-line treatments, respectively.

This study provides insight into current treatment patterns for mTNBC in Japan. The cost-benefit balance worsens with later-line treatment and a high unmet need for mTNBC drug treatment remains.

Eribulin is a non-taxane synthetic analogue approved in many countries as third-line treatment for the treatment of patients with metastatic breast cancer. In addition to its mitotic property, eribulin has non-mitotic properties including but not limited to, its ability to induce phenotypic reversal of epithelial to mesenchymal transition, vascular remodelling, reduction in immunosuppressive tumour microenvironment. Since approval, there has been a surge in studies investigating the application of eribulin as an earlier-line treatment and also in combination with other agents such as immunotherapy and targeted therapy across all breast cancer sub-types, including hormone receptor positive, HER2 positive and triple negative breast cancer, many demonstrating promising activity. This review will focus on the application of eribulin in the treatment of metastatic breast cancer across all subtypes including its role as an earlier-line agent, its toxicity profile, and potential future directions.

Treatment of advanced triple-negative breast cancer (TNBC) is a great challenge in clinical practice. The immune checkpoints are a category of immunosuppressive molecules that cancer could hijack and impede anti-tumor immunity. Targeting immune checkpoints, such as anti-programmed cell death 1 (PD-1) therapy, is a promising therapeutic strategy in TNBC. The efficacy and safety of PD-1 monoclonal antibody (mAb) with chemotherapy have been validated in TNBC patients. However, the precise mechanisms underlying the synergistic effect of chemotherapy and anti-PD-1 therapy have not been elucidated, causing the TNBC patients that might benefit from this combination regimen not to be well selected. In the present work, we found that IL-23, an immunological cytokine, is significantly upregulated after chemotherapy in TNBC cells and plays a vital role in enhancing the anti-tumor immune response of cytotoxic T cells (CTLs), especially in combination with PD-1 mAb. In addition, the combination of IL-23 and PD-1 mAb could synergistically inhibit the expression of Phosphoinositide-3-Kinase Regulatory Subunit 1 (PIK3R1), which is a regulatory subunit of PI3K and inhibit p110 activity, and promote phosphorylation of AKT in TNBC-specific CTLs. Our findings might provide a molecular marker that could be used to predict the effects of combination chemotherapy therapy and PD-1 mAb in TNBC.

Molecular sub-characterization of triple-negative breast cancer (TNBC) has great therapeutic and possibly prognostic implications. The primary aim of this study was to investigate the incidence of luminal androgen receptor (LAR) subtype of TNBC and secondary aims were sub-categorization and clinico-pathologic correlation of LAR breast cancers. Retrospective study (January 2008 and 31st of December 2018) consisting of 157 TNBC patients. Androgen receptor (AR) expression was measured by immunohistochemical analysis. One percent cutoff was set as a positive expression. Sub-categorization was done on the basis of EGFR (> 15% of tumor cells) and Ki-67 expression (low- < 11%, intermediate- 11-20%, and high- > 21%). AR expression was correlated with various clinico-pathologic features and outcomes of the patients. The incidence of AR expression in TNBC was 24.8%. Considering different thresholds of > 5%, > 10%, and > 20% immunostaining, the incidence of AR positivity was 18.4, 15.2, and 11.5% respectively. The incidence of Ki-67 (p = 0.89) and EGFR (p = 0.643) expression did not differ significantly in AR-positive and -negative TNBC. Based on EGFR expression 19, 67 and 14% patients were categorized as low, intermediate, and high risk respectively. Low-risk (p ≤ 0.001) and low-grade (p = 0.014) tumors were more likely to have > 10% AR expression. Clinico-pathological profile, response to neoadjuvant chemotherapy, disease-free survival (p = 0.458), and overall survival (p = 0.806) did not significantly differ between AR expressing and negative TNBC. On multivariate analysis, only tumor staging was a significant predictor of survival (p = 0.012) and AR expression of > 10% revealed a trend towards improved survival (p = 0.07). When considering only AR-positive TNBC, AR expression of > 10% (p = 0.038), distant metastases (p = 0.003), and EGFR status (p = 0.024) were significantly associated with survival. AR expression does not seem to very strongly correlate with prognosis in TNBC and further studies could focus more on its predictive role in deciding anti-androgen therapy.

Metastatic triple-negative breast cancer (TNBC) is aggressive with poor median overall survival (OS) ranging from 8 to 13 months. There exists considerable heterogeneity in survival at the individual patient level. To better understand the survival heterogeneity and improve risk stratification, our study aims to identify the factors influencing survival, utilizing a large patient sample from the National Cancer Database (NCDB).

Women diagnosed with metastatic TNBC from 2010 to 2020 in the NCDB were included. Demographic, clinicopathological, and treatment data and overall survival (OS) outcomes were collected. Kaplan-Meier curves were used to estimate OS. The log-rank test was used to identify OS differences between groups for each variable in the univariate analysis. For the multivariate analysis, the Cox proportional hazard model with backward elimination was used to identify factors affecting OS. Adjusted hazard ratios and 95% confidence intervals are presented.

In this sample, 2273 women had a median overall survival of 13.6 months. Factors associated with statistically significantly worse OS included older age, higher comorbidity scores, specific histologies, higher number of metastatic sites, presence of liver or other site metastases in those with only one metastatic site (excluding brain metastases), presence of cranial and extra-cranial metastases, lack of chemotherapy, lack of immunotherapy, lack of surgery to distant sites, lack of radiation to distant sites, and receipt of palliative treatment to alleviate symptoms. In the multivariate analysis, comorbidity score, histology, number of metastatic sites, immunotherapy, and chemotherapy had a statistically significant effect on OS.

Through NCDB analysis, we have identified prognostic factors for metastatic TNBC. These findings will help individualize prognostication at diagnosis, optimize treatment strategies, and facilitate patient stratification in future clinical trials.

Breast cancer is the second leading contributor to the age-standardized mortality rate, for both sexes and all ages worldwide. In Europe and the United States, it is the second leading cause of mortality, with an incidence rate of about 2.6 million cases per year. Noscapine, a well-known alkaloid used as a cough suppressant, demonstrated anti-tumor effects by triggering apoptosis in various cancer cell lines and has the potential to become another ally against breast, ovarian, colon, and gastric cancer, among other types of malignancy. Apoptosis plays a crucial role in the treatment of cancer. Noscapine affected BAX, CASP8, CASP9, NFKBIA, and RELA gene and protein expression in the MCF-7 and MDA-MB-231 cell lines. Gene expression was higher in tumor than in normal tissue, including the BAX expression levels in lung, ovary, endometrium, colon, stomach, and glioblastoma patients; BCL2L1 expression in endometrium, colon, and stomach patients; CASP8 gene expression levels in lung, endometrium, colon, stomach, and glioblastoma patients; RELA in colon, stomach, and glioblastoma patients; and NFKBIA in glioblastoma patients. It can be concluded that noscapine affected genes and proteins related to apoptosis in cancer cell lines and several types of cancer patients.

Metal complexes have gained significant attention as potential anti-cancer agents. The anti-cancer activity of [Co(phen)2(MeATSC)](NO3)3•1.5H2O•C2H5OH 1 (where phen = 1,10-phenanthroline and MeATSC = 9-anthraldehyde-N(4)-methylthiosemicarbazone) and [Cu(acetylethTSC)Cl]Cl•0.25C2H5OH 2 (where acetylethTSC = (E)-N-ethyl-2-[1-(thiazol-2-yl)ethylidene]hydrazinecarbothioamide) was investigated by analyzing DNA cleavage activity. The cytotoxic effect was analyzed using CCK-8 viability assay. The activities of caspase 3/7, 9, and 1, reactive oxygen species (ROS) production, cell cycle arrest, and mitochondrial function were further analyzed to study the cell death mechanisms. Complex 2 induced a significant increase in nicked DNA. The IC50 values of complex 1 were 17.59 μM and 61.26 μM in cancer and non-cancer cells, respectively. The IC50 values of complex 2 were 5.63 and 12.19 μM for cancer and non-cancer cells, respectively. Complex 1 induced an increase in ROS levels, mitochondrial dysfunction, and activated caspases 3/7, 9, and 1, which indicated the induction of intrinsic apoptotic pathway and pyroptosis. Complex 2 induced cell cycle arrest in the S phase, ROS generation, and caspase 3/7 activation. Thus, complex 1 induced cell death in the breast cancer cell line via activation of oxidative stress which induced apoptosis and pyroptosis while complex 2 induced cell cycle arrest through the induction of DNA cleavage.

RAS guanyl releasing protein 1 (RASGRP1) is a guanine nucleotide exchange factor (GEF) characterized by the presence of a RAS superfamily GEF domain. It functions as a diacylglycerol (DAG)-regulated nucleotide exchange factor, specifically activating RAS through the exchange of bound GDP for GTP. Activation of RAS by RASGRP1 has a wide range of downstream effects at the cellular level. Thus, it is not surprising that many diseases are associated with RASGRP1 disorders. Here, we present an overview of the structure and function of RASGRP1, its crucial role in the development, expression, and regulation of immune cells, and its involvement in various signaling pathways. This review comprehensively explores the relationship between RASGRP1 and various diseases, elucidates the underlying molecular mechanisms of RASGRP1 in each disease, and identifies potential therapeutic targets. This study provides novel insights into the role of RASGRP1 in insulin secretion and highlights its potential as a therapeutic target for diabetes. The limitations and challenges associated with studying RASGRP1 in disease are also discussed.

Immunotherapy is applied to breast cancer to resolve the limitations of survival gain in existing treatment modalities. With immunotherapy, a tumor can be classified into immune-inflamed, excluded and desert based on the distribution of immune cells. We assessed the clinicopathological features, each subtype's prognostic value and differentially expressed proteins between immune subtypes.

Immune subtyping and proteomic analysis were performed on 56 breast cancer cases with neoadjuvant chemotherapy. The immune subtyping was based on the level of tumor-infiltrating lymphocytes (TILs) and Klintrup criteria. If the level of TILs was ≥ 10%, it was classified as immune-inflamed type without consideration of the Klintrup criteria. In cases of 1-9% TIL, Klintrup criteria 1-3 were classified as the immune-excluded subtype and Klintrup criteria not available (NA) was classified as NA. Cases of 1% TILs and Klintrup 0 were classified as the immune-desert subtype. Mass spectrometry was used to identify differentially expressed proteins in formalin-fixed paraffin-embedded biopsy tissues.

Of the 56 cases, 31 (55%) were immune-inflamed, 21 (38%) were immune-excluded, 2 (4%) were immune-desert and 2 (4%) were NA. Welch's t-test revealed two differentially expressed proteins between immune-inflamed and immune-excluded/desert subtypes. Coronin-1A was upregulated in immune-inflamed tumors (adjusted p = 0.008) and α-1-antitrypsin was upregulated in immune-excluded/desert tumors (adjusted p = 0.008). Titin was upregulated in pathologic complete response (pCR) than non-pCR among immune-inflamed tumors (adjusted p = 0.036).

Coronin-1A and α-1-antitrypsin were upregulated in immune-inflamed and immune-excluded/desert subtypes, respectively. Titin's elevated expression in pCR within the immune-inflamed subtype may indicate a favorable prognosis. Further studies involving large representative cohorts are necessary to validate these findings.

Triple-negative breast cancer (TNBC) has been documented as the most aggressive subtype of breast cancer. This study aimed to analyze antitumor and protumor immune activities, and their ratios as significant prognostic biomarkers in metastatic TNBC (mTNBC).

A multicenter cohort study was conducted among 103 de novo mTNBC patients. The expression of CD8 and CD163 was evaluated using immunohistochemistry staining, CD4 and FOXP3 using double-staining immunohistochemistry, and PD-L1 using immunohistochemistry and RT-PCR.

Multivariate analysis revealed that high CD4/FOXP3 (HR 1.857; 95% CI 1.049-3.288; p = 0.034) and the CD8/CD163 ratio (HR 2.089; 95% CI 1.174-3.717; p = 0.012) yield significantly improved 1 year overall survival (OS). Kaplan-Meier analysis showed that high levels of CD4 (p = 0.023), CD8 (p = 0.043), CD4/FOXP3 (p = 0.016), CD8/FOXP3 (p = 0.005), CD8/CD163 (p = 0.005) ratios were significantly associated with higher rate of 1 year OS. Furthermore, 1 year OS was directly correlated with antitumor CD4 (R = 0.233; p = 0.018) and CD8 (R = 0.219; p = 0.026) and was indirectly correlated with protumor CD163 and FOXP3 through CD4/FOXP3 (R = 0.282; p = 0.006), CD4/CD163 (R = 0.239; p = 0.015), CD8/FOXP3 (R = 0.260; p = 0.008), and CD8/CD163 (R = 0.258; p = 0.009).

This is the first study to demonstrate that high levels of CD4/FOXP3 and CD8/CD163 significantly improved the 1 year OS in de novo mTNBC patients. Thus, we recommend the application of these markers as prognosis determination and individual treatment decision.

Long-chain noncoding RNA (lncRNA), LINC01569, is important for regulating the extracellular matrix, which affects cell migration. However, its involvement in the occurrence and development of triple-negative breast cancer (TNBC) remains unclear.

This study is aimed to investigate the role of LINC01569 on TNBC.

Online database was used for clinical data analysis. Cell viability and migration capability were monitored using cell counting kit-8 and transwell assays, respectively. Luciferase reporter assay and RNA pull-down were used to confirm the binding capability between noncoding RNAs and filamin A-interacting protein 1-like (FILIP1L). Western blotting was used to determine the protein content.

Compared with normal breast tissue, LINC01569 was significantly reduced in patients with TNBC subtype, and LINC01569 expression gradually decreased with the progression of tumor stage. Patients with TNBC with high lncRNA LINC01569 levels had a better prognosis than did patients with low LINC01569 levels. LINC01569 overexpression inhibited the migration capability, whereas siRNA-mediated LINC01569 downregulation promoted the migration capability in TNBC cells. Using ENCORI and lncRNA SNP online databases, miR-300 was screened as the potential sponge of LINC01569. The binding of LINC01569 to miR-300 was confirmed using the dual-luciferase reporter and RNA pull-down assays. miR-300 was negatively correlated with LINC01569, and miR-300 mimics eliminated the anti-proliferation and anti-migration effects of LINC01569 on TNBC cells. Additionally, FILIP1L was further verified as the downstream target of miR-300. miR-300 mimics blocked LINC01569 upregulation-mediated elevation of FILIP1L. Importantly, the anti-tumor effects mediated by LINC01569 overexpression were abolished by miR-300 mimics and further restored by FILIP1L upregulation.

LINC01569 was expressed at a low level in TNBC and could sponge miR-300 to promote FILIP1L expression, reducing the proliferation and metastasis capability of TNBC. Thus, LINC01569 might be a useful biomarker in the diagnosis and prognosis of metastatic TNBC.

Severe calorie restriction, in the form of cyclic fasting or fasting-mimicking diets (FMDs), boosts the antitumor activity of cytotoxic chemotherapy in mouse models of triple-negative breast cancer (TNBC). This effect is mostly mediated by fasting/FMD-induced reduction of plasma glucose concentration and by a boost in antitumor immunity. However, clinical evidence that cyclic FMD may impact on the outcomes of advanced TNBC (aTNBC) patients is lacking. We compared the overall survival (OS) of 14 aTNBC patients receiving first-line carboplatin-gemcitabine plus cyclic FMD in the context of the NCT03340935 trial with the OS of 76 consecutive aTNBC patients treated with carboplatin-based chemotherapy alone at Fondazione IRCCS Istituto Nazionale dei Tumori. Multivariable Cox regression models were used to adjust the prognostic impact of FMD for other prognostic variables. Patients undergoing cyclic FMD in combination with carboplatin-gemcitabine had better OS when compared to patients receiving chemotherapy alone (median OS 30.3 months, 95% CI 18-NR, vs 17.2 months, 95% CI 15.3-25.1, log-rank P value .041). Multivariable analysis confirmed an association between FMD use and better OS (HR: 0.40; 95% CI: 0.19-0.86; P = .019) also after propensity score-based matching according to patient ECOG PS and the presence of de novo metastatic disease (HR: 0.41; 95% CI: 0.21-0.83; P = .013). Cyclic FMD in combination with first-line chemotherapy may improve clinical outcomes in aTNBC patients. Our study paves the way for conducting phase II trials to investigate if cyclic FMD can increase the antitumor activity/efficacy of chemotherapy or chemoimmunotherapy in patients with early-stage TNBC or aTNBC.

This comprehensive review aims to provide timely and relevant insights into the current therapeutic landscape for triple-negative breast cancer (TNBC) and the molecular features underlying this subtype. It emphasizes the need for more reliable biomarkers to refine prognostication and optimize therapy, considering the aggressive nature of TNBC and its limited targeted treatment options.

The review explores the multidisciplinary management of early TNBC, which typically involves systemic chemotherapy, surgery, and radiotherapy. It highlights the emergence of immune checkpoint inhibitors (ICIs), poly(ADP-ribose) polymerase (PARP) inhibitors, and antibody-drug conjugates (ADCs) as promising therapeutic strategies for TNBC. Recent clinical trials investigating the use of ICIs in combination with chemotherapy and the approval of pembrolizumab and atezolizumab for PD-L1-positive metastatic TNBC are discussed. The efficacy of PARP inhibitors and ADCs in treating TNBC patients with specific genetic alterations is also highlighted.

The findings discussed in this review have significant implications for clinical practice and research in TNBC. The identification of distinct molecular subtypes through gene expression profiling has enabled a better understanding of TNBC heterogeneity and its clinical implications. This knowledge has the potential to guide treatment decisions, as different subtypes display varying responses to neoadjuvant chemotherapy. Furthermore, the review emphasizes the importance of developing reliable genomic and transcriptomic signatures as biomarkers to refine patient prognostication and optimize therapy selection in TNBC. Integrating these signatures into clinical practice may lead to more personalized treatment approaches, improving outcomes for TNBC patients.

Triple negative breast cancer (TNBC), a highly aggressive subtype of breast cancer, accounts for 15 % of all diagnosed breast cancers. This group, which has the worst clinical outcome, high recurrence rate and poor prognosis, does not benefit from specific treatment. Therefore, there is a need to develop more effective biomarker and therapeutic strategies especially for this group. A positive level of immunity has been found to be associated with patient survival in various organ cancers. More specifically, tumor infiltrating lymphocytes (TIL) have been documented to have strong prognostic value. The programmed cell death 1 (PD 1) protein on the surface of T lymphocytes is activated by the Programmed cell death ligand 1 (PD-L1) protein on the cancer cell surface. PD- L1 is thought to form a pathway that results in suppression of antitumor responses when activated. Patients with breast cancer (BC) who underwent resection without neoadjuvant chemotherapy between 2010 and 2020 were included in this study. Of the 302 BCs examined, 21 constitute the group with TNBC. In our study, the mean age of the Triple positive breast cancer (TPBC) and TNBC groups was similar (55.67 ± 12.61 vs. 53.23 ± 8.21, p = 0.384). There was no significant correlation between TPBC and TNBC and tumor size, lymph node, histological grade, and PD-L1 positivity in the center of the tumor (all p-value >.05). It was observed that tumor stage was higher in patients with TNBC than in patients with TPBC (19 % vs. 1.1 %, p = .002). The Ki 67 proliferation index was found to be higher in patients with TNBC than in patients with TPBC (90.5 % vs. 41.8 %, p .001). Although not statistically significant, clinically, CD 3 and CD 8 immune scores with high tumor margin were higher in patients with TNBC than in patients with TPBC (90.4 % vs, 9.6 % and 85.7 % vs. 14.3 %, respectively). Positive expression of PD-L1 at the tumor margin was significantly higher in patients with TNBC than patients with TPBC (20.3 % vs, 52.4 %, p = .002). By Kaplan-Meier analysis, the survival distribution of CD 3 and CD 8 immunoscore, tumor central and margin PD-L1 values were compared. Mean follow-up was 136.18 months (range, 1 - 144 months); and the 10-year Overall Survival (OS) estimate for the population was 90.9 % (95 % CI, 85.5 - 96.7). In this study, this difference was not statistically significant according to the log-rank test. In this study, we aimed to evaluate the relationship between CD 3, CD 8 T lymphocyte immune score and PD-L1 expression at the tumor center and margin in TNBC, the prognostic value and clinicopathological significance of this relationship.

Sacituzumab govitecan has been recently approved by the USFDA and EMA for the treatment of patients with metastatic triple-negative breast cancer (mTNBC). We report real-world safety and effectiveness in patients with mTNBC receiving sacituzumab govitecan treatment at a breast cancer centre in Germany.

Data from patients who had received sacituzumab govitecan as treatment for mTNBC, in both de novo and relapsed disease, at the Kliniken Essen-Mitte, Essen, Germany, were collected through institutional records. Data were analysed for safety parameters and survival outcomes and reported using descriptive statistics.

Patients (N = 43) received a median (range) of 5 (1-28) cycles of sacituzumab govitecan and were followed up for a median of 12.9 months. The most reported adverse events (AEs) of any grade were alopecia (n = 39; 90.7%), diarrhoea (n = 16; 37.2%), fatigue (n = 15, 34.9%), anaemia (n = 15, 34.9%) and neutropenia (n = 14, 32.6%). AEs ⩾ Grade 3 with the highest incidence were neutropenia (n = 12; 27.9%) and diarrhoea (n = 8; 18.6%). In eight (18.6%) patients, dose of sacituzumab govitecan dose was reduced due to patients' clinical condition prior to commencing treatment; in further 17 (39.5%) patients, sacituzumab govitecan dose had to be reduced or treatment interrupted on account of AEs associated with the drug after treatment had commenced. Median progression-free survival and median overall survival were calculated to be 5.0and 13.1 months, respectively.

The real-world safety and effectiveness profile of sacituzumab govitecan in patients with mTNBC are in line with clinical trial data. Further studies are required to guide optimal use of sacituzumab govitecan against mTNBC, especially in context of management of accompanying AEs.

As the most aggressive breast cancer, triple-negative breast cancer (TNBC) is still incurable and very prone to metastasis. The transform growth factor β (TGF-β)-induced epithelial-mesenchymal transition (EMT) is crucially involved in the growth and metastasis of TNBC. This study reported that a natural compound isotoosendanin (ITSN) reduced TNBC metastasis by inhibiting TGF-β-induced EMT and the formation of invadopodia. ITSN can directly interact with TGF-β receptor type-1 (TGFβR1) and abrogated the kinase activity of TGFβR1, thereby blocking the TGF-β-initiated downstream signaling pathway. Moreover, the ITSN-provided inhibition on metastasis obviously disappeared in TGFβR1-overexpressed TNBC cells in vitro as well as in mice bearing TNBC cells overexpressed TGFβR1. Furthermore, Lys232 and Asp351 residues in the kinase domain of TGFβR1 were found to be crucial for the interaction of ITSN with TGFβR1. Additionally, ITSN also improved the inhibitory efficacy of programmed cell death 1 ligand 1 (PD-L1) antibody for TNBC in vivo via inhibiting the TGF-β-mediated EMT in the tumor microenvironment. Our findings not only highlight the key role of TGFβR1 in TNBC metastasis, but also provide a leading compound targeting TGFβR1 for the treatment of TNBC metastasis. Moreover, this study also points out a potential strategy for TNBC treatment by using the combined application of anti-PD-L1 with a TGFβR1 inhibitor.

Triple-negative breast cancer (TNBC) accounts for almost 15% of all diagnosed breast cancers and often presents high rates of relapses and metastases, with generally poor prognosis despite multiple lines of treatment. Immunotherapy has radically changed the approach of clinicians towards TNBC in the last two to three years, even if targeted and specific therapeutic options are still missing; this unmet need is further justified by the extreme molecular and clinical heterogeneity of this subtype of breast cancer and by the weak response to both single-agent and combined therapies. In March 2023, the National Comprehensive Cancer Network (NCCN), the main association of cancer centers in the United States, released the last clinical practice guidelines, with an update on classic and novel approaches in the field of breast cancer. The purpose of this comprehensive review is to summarize the latest findings in the setting of metastatic TNBC treatment, focusing on each category of drugs approved by the Food and Drug Administration (FDA) and included in the NCCN guidelines. We also introduce part of the latest published studies, which have reported new and promising molecules able to specifically target some of the biomarkers involved in TNBC pathogenesis. We searched the PubMed and Scopus databases for free full texts reported in the literature of the last 5 years, using the words "triple-negative breast cancer" or "TNBC" or "basal-like". The articles were analyzed by the authors independently and double-blindly, and a total of 114 articles were included in the review.

Tissue factor (TF) is a protein that plays a critical role in blood clotting, but recent research has also shown its involvement in cancer development and progression. Herein, we provide an overview of the structure of TF and its involvement in signaling pathways that promote cancer cell proliferation and survival, such as the PI3K/AKT and MAPK pathways. TF overexpression is associated with increased tumor aggressiveness and poor prognosis in various cancers. The review also explores TF's role in promoting cancer cell metastasis, angiogenesis, and venous thromboembolism (VTE). Of note, various TF-targeted therapies, including monoclonal antibodies, small molecule inhibitors, and immunotherapies have been developed, and preclinical and clinical studies demonstrating the efficacy of these therapies in various cancer types are now being evaluated. The potential for re-targeting TF toward cancer cells using TF-conjugated nanoparticles, which have shown promising results in preclinical studies is another intriguing approach in the path of cancer treatment. Although there are still many challenges, TF could possibly be a potential molecule to be used for further cancer therapy as some TF-targeted therapies like Seagen and Genmab's tisotumab vedotin have gained FDA approval for treatment of cervical cancer. Overall, based on the overviewed studies, this review article provides an in-depth overview of the crucial role that TF plays in cancer development and progression, and emphasizes the potential of TF-targeted and re-targeted therapies as potential approaches for the treatment of cancer.

Despite substantial improvements in breast cancer (BC) treatment there is still an urgent need to find alternative treatment options to improve the outcomes for patients with advanced-stage disease. Photodynamic therapy (PDT) is gaining a lot of attention as a BC therapeutic option because of its selectivity and low off-target effects. However, the hydrophobicity of photosensitizers (PSs) impairs their solubility and limits the circulation in the bloodstream, thus representing a major challenge. The use of polymeric nanoparticles (NPs) to encapsulate the PS may represent a valuable strategy to overcome these issues. Herein, we developed a novel biomimetic PDT nanoplatform (NPs) based on a polymeric core of poly(lactic-co-glycolic)acid (PLGA) loaded with the PS meso-tetraphenylchlorin disulfonate (TPCS2a). TPCS2a@NPs of 98.89 ± 18.56 nm with an encapsulation efficiency percentage (EE%) of 81.9 ± 7.92% were obtained and coated with mesenchymal stem cells-derived plasma membranes (mMSCs) (mMSC-TPCS2a@NPs, size of 139.31 ± 12.94 nm). The mMSC coating armed NPs with biomimetic features to impart long circulation times and tumor-homing capabilities. In vitro, biomimetic mMSC-TPCS2a@NPs showed a decrease in macrophage uptake of 54% to 70%, depending on the conditions applied, as compared to uncoated TPCS2a@NPs. Both NP formulations efficiently accumulated in MCF7 and MDA-MB-231 BC cells, while the uptake was significantly lower in normal breast epithelial MCF10A cells with respect to tumor cells. Moreover, encapsulation of TPCS2a in mMSC-TPCS2a@NPs effectively prevents its aggregation, ensuring efficient singlet oxygen (1O2) production after red light irradiation, which resulted in a considerable in vitro anticancer effect in both BC cell monolayers (IC50 < 0.15 µM) and three-dimensional spheroids.

Patients with triple-negative breast cancer (TNBC) have dismal prognoses due to the lack of therapeutic targets and susceptibility to lymph node (LN) metastasis. Therefore, it is essential to develop more effective approaches to identify early TNBC tissues and LNs. In this work, a magnetic resonance imaging (MRI) contrast agent (Mn-iCOF) was constructed based on the Mn(II)-chelated ionic covalent organic framework (iCOF). Because of the porous structure and hydrophilicity, the Mn-iCOF has a high longitudinal relaxivity (r₁) of 8.02 mM^-1 s^-1 at 3.0 T. For the tumor-bearing mice, a lower dose (0.02 mmol [Mn]/kg) of Mn-iCOF demonstrated a higher signal-to-noise ratio (SNR) value (1.8) and longer retention time (2 h) compared to a 10-fold dose of commercial Gd-DOTA (0.2 mmol [Gd]/kg). Moreover, the Mn-iCOF can provide continuous and significant MR contrast for the popliteal LNs within 24 h, allowing for accurate evaluation and dissection of LNs. These excellent MRI properties of the Mn-iCOF may open new avenues for designing more biocompatible MRI contrast agents with higher resolutions, particularly in the diagnosis of TNBC.