Search Results (282)

Bacteria-mediated cancer therapy represents a novel and promising strategy for targeted drug delivery to solid tumors. Multiple studies have demonstrated that various Bifidobacterium species can selectively colonize the hypoxic microenvironments characteristic of solid tumors. Leveraging this property, Bifidobacterium has been explored as a delivery vector for a range of anti-cancer approaches such as immunotherapy, nanoformulated chemotherapeutics, and gene therapy. Notably, anti-angiogenic genes such as endostatin and tumstatin have been successfully delivered to colorectal tumors using Bifidobacterium infantis and Bifidobacterium longum, respectively. Additionally, Bifidobacterium bifidum has been employed to transport doxorubicin and paclitaxel nanoparticles to breast and lung tumor sites. Furthermore, both Bifidobacterium longum and Bifidobacterium bifidum have been utilized to deliver nanoparticles that act as synergistic agents for high-intensity focused ultrasound (HIFU) therapy, significantly enhancing tumor ablation, particularly in triple-negative breast cancer (TNBC) models. While these pre-clinical findings are highly encouraging, further clinical research is essential. Specifically, studies are needed to investigate the colonization dynamics of different Bifidobacterium species across various tumor types and to evaluate their potential in delivering diverse cancer therapies in human patients. Full article

Of breast cancers, the triple-negative subtype (TNBC) is characterized by aggressive behavior, poor prognosis and limited treatment options due to its high molecular heterogeneity. Since insufficient programmed cell death response is a major hallmark of cancer, here we searched for apoptosis-related biomarkers of prognostic potential in TNBC. The expression of the pro-apoptotic caspase 8, cytochrome c, caspase 3, the anti-apoptotic BCL2 and the caspase-independent mediator, apoptosis-inducing factor-1 (AIF1; gene AIFM1) was tested in TNBC both in silico at transcript and protein level using KM-Plotter, and in situ in our clinical TNBC cohort of 103 cases using immunohistochemistry. Expression data were correlated with overall survival (OS), recurrence-free survival (RFS) and distant metastasis-free survival (DMFS). We found that elevated expression of the executioner apoptotic factors AIF1 and caspase 3, and of BCL2, grants significant OS advantage within TNBC, both at the mRNA and protein level, particularly for chemotherapy-treated vs untreated patients. The dominantly cytoplasmic localization of AIF1 and cleaved-caspase 3 proteins in primary TNBC suggests that chemotherapy may recruit them from the cytoplasmic/mitochondrial stocks to contribute to improved patient survival in proportion to their expression. Our results suggest that testing for the expression of AIF1, caspase 3 and BCL2 may identify partly overlapping TNBC subgroups with favorable prognosis, warranting further research into the potential relevance of apoptosis-targeting treatment strategies. Full article

Background: TNBC patients respond poorly to chemotherapy, leading to high mortality rates and a worsening prognosis. Here, we investigated the effect of M-I on TNBC tumor growth suppression and its potential mechanisms. Methods: Signaling pathways were analyzed to study the effect of M-I on TNBC cells (human MDA-MB-231 and mouse 4T1). We used orthotopic mouse models to examine the anti-tumor efficacy of M-I. Tumor volume and the status of tumor-associated macrophages (TAMs) were assessed by qRT-PCR or FACS analysis. Results: We found a significant dose- and time-dependent inhibition of TNBC cell proliferation following treatment with M-I. Cell cycle analysis revealed a shortened S phase in M-I-treated cells and downregulation of AURKA, PLK1, CDC25c, CDK1, and cyclinB1. Furthermore, M-I treatment reduced the expression of pSTAT3, cyclinD1, and c-Myc in TNBC cells. To evaluate the anti-tumor efficacy of M-I, we employed orthotopic TNBC mouse models and observed a significant reduction in tumor growth without measurable toxicity. Next, we analyzed RNA from control and M-I-treated tumors to further assess the status of TAMs and observed a significant decrease in M2-like macrophages in the M-I-treated group. Immortalized bone marrow-derived mouse macrophages (iMacs) exposed to conditioned media (CM) of TNBC cells with or without M-I treatment indicated that the M-I treated CM of TNBC cells significantly reduce the M2phenotype in iMacs. Mechanistically, we found that M-I specifically targets the IL-4/MAPK signaling axis to reduce immunosuppressive M2 macrophage polarization. Conclusions: Our study reveals a novel mechanism by which M-I inhibits TNBC cell proliferation by regulating intracellular signaling and altering TAMs in the tumor microenvironment and highlights its potential as a promising candidate for TNBC therapy. Full article

Background/Objectives: The tumor microenvironment (TME) plays a critical role in cancer progression by shaping immune responses and influencing patient outcomes. We hypothesized that the relative proximity of specific immune cell pairs to cancer cells within the TME could help predict their pro- or anti-tumor functions and reflect clinically relevant immune dynamics. Methods: We analyzed imaging mass cytometry (IMC) data from lung adenocarcinoma (LUAD) and triple-negative breast cancer (TNBC) cohorts. For each immune cell pair, we calculated a relative distance (RD) score, which quantifies the spatial difference in proximity to cancer cells. We assessed the prognostic and predictive significance of these RD-scores by comparing them with conventional features such as cell fractions, densities, and individual cell distances. To account for variations in cell abundance, we also derived normalized RD-scores (NRD-scores). Results: RD-scores were more strongly associated with overall patient survival than standard immunological metrics. Among all immune cell pairs, the RD-score comparing the proximity of B cells to that of intermediate monocytes showed the most significant association with improved survival. In TNBC, RD-scores also improved the distinction between responders and non-responders to immunochemotherapy and chemotherapy. Normalized RD-scores reinforced these findings by minimizing the influence of cell density and further highlighting the importance of immune cell spatial relationships. Conclusions: RD-scores offer a spatially informed biomarker that outperforms traditional metrics in predicting survival and treatment response. This approach provides a new perspective on immune cell behavior in the TME and has potential utility in guiding personalized cancer therapies and patient stratification. Full article

Artocarpus heterophyllus (jackfruit) is widely distributed in subtropical and tropical regions, and some phytochemicals isolated from this species have demonstrated anti-proliferative effects. However, its impact on triple-negative breast cancer (TNBC) and HPV-related cervical cancer models remains unclear. This study evaluated the phytochemical profile and anticancer activity of an ethanolic extract from A. heterophyllus leaves (AHEE) in the TNBC cell line MDA-MB-231 and in the HPV-16⁺ murine cancer cell line TC-1. Phytochemical screening and spectroscopic analyses (UV-Vis, IR, ¹H, and ¹³C NMR) revealed the presence of tannins, alkaloids, steroids, coumarins, and flavone-type flavonoids, with a total phenolic content of 3.34 µg GAE/mg and flavonoid content of 0.44 mg QE/g extract. In 2D cultures, AHEE reduced cell viability by 49% in TC-1 and 24% in MDA-MB-231 at 300 µg/mL, inhibited colony formation and migration in TC-1, and impaired survival but not migration in MDA-MB-231. In 3D cultures, 250 µg/mL inhibited proliferation, migration, and anchorage-independent growth in both cell lines. Furthermore, the combination of AHEE with one-fifth of the IC₅₀ of doxorubicin or cisplatin produces an effect comparable to that observed with the full IC₅₀ of these drugs. These findings suggest that AHEE possesses anticancer activity with cell-type-specific effects and highlight its potential as an adjuvant therapy. Further studies are warranted to elucidate its mechanisms of action. Full article

Triple-negative breast cancer (TNBC) is a heterogenous group of breast tumors. This type of breast tumor is relatively difficult to manage, due to the lack of expression of Hormone Receptors (HR) and human epidermal growth factor receptor (HER2). Efforts have been made to understand the factors involved in determining how a triple-negative breast tumor responds to therapy. The standard of treatment in most cases today is a combined modality of immune checkpoint inhibitors (ICIs) and chemotherapy with agents such as anti-mitotic (taxanes) or DNA-damaging agents (alkylating agents, cyclophosphamides, platin salts). In this study, we investigated the predictive and prognostic factors for TNBC, in the neoadjuvant setting; understanding each patient’s response before treatment initiation is crucial to guiding the subsequent approach and finally improving patient outcomes. We focused on tumor-infiltrating lymphocytes at the site of the primary tumor (TILs), circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), the mutational status of protein 53 (p53), and Ki-67, investigating the potential roles of these factors in predicting responses to anti-cancer agents. Full article

Triple-negative breast cancer (TNBC) frequently evades immune recognition and elimination, resulting in an immunosuppressive microenvironment. The phagocytic activity of tumor-associated macrophages underscores the development of nanomaterials as a promising strategy to target these macrophages and modulate their polarization, thereby advancing immunotherapy against TNBC. This research developed functional polymers that are complexed with therapeutic molecules as a coating strategy for iron oxide nanoparticles. An arginine-based poly (ester urea urethane) polymer complexed with a macrophage-polarizing molecule (APU-R848) could provide a synergistic effect with iron oxide nanoparticles (IONPs) to stimulate the M1-polarization of macrophages at the tumor site, resulting in a versatile nano-platform for immune regulation of TNBC. In the 4T1 in vivo breast tumor model, the APU-R848-IONPs demonstrated an improved intratumoral biodistribution compared to IONPs without a polymer coating. APU-R848-IONPs significantly reversed the immune-suppressive tumor environment by reducing the M2/M1 macrophage phenotype ratio by 51%, associated with an elevated population of cytotoxic T cells and a significantly enhanced production of tumoricidal cytokines. The activated immune response induced by APU-R848-IONP resulted in a significant anti-tumor effect, demonstrating an efficacy that was more than 3.2-fold more efficient compared to the controls. These immune-regulatory pseudo-protein-coated iron oxide nanoparticles represent an effective nano-strategy for macrophages’ regulation and the activation of anti-tumor immunity, providing a new treatment modality for triple-negative breast cancer. Full article

Background: Targeted therapies, such as endocrine agents, have significantly improved outcomes for patients with estrogen receptor alpha-positive (ERα+) breast cancer. Unfortunately, for patients with triple-negative breast cancer (TNBC), which lack expression of ERα and HER2, there remains a dearth of targeted adjuvant agents. We discovered that estrogen receptor beta (ERβ) is expressed in approximately 20% of TNBC cases, and its activation has been shown to inhibit proliferation, invasion, and migration in preclinical models. However, it remains unclear whether ERβ-targeted therapies maintain efficacy following the development of chemoresistance. Methods: To address this question, we generated ERβ+ TNBC cell line models with acquired resistance to paclitaxel or doxorubicin. We then assessed their response to ERβ-targeted therapies and analyzed transcriptomic changes associated with chemoresistance and ERβ ligand treatment. Results: Chemotherapy-resistant ERβ+ TNBC cells retained sensitivity to ERβ-targeted therapies and, in some cases, exhibited enhanced responsiveness. ERβ expression did not compromise chemotherapy efficacy in treatment-naïve cells. Chemotherapy-resistant cells had a vastly altered transcriptome and surprisingly, a heavily reduced ERβ transcriptome, compared to sensitive cells despite the maintenance of ERβ-driven anti-neoplastic activity. Conclusions: These findings suggest that ERβ remains a relevant drug target in chemotherapy-refractory disease and has aided in the refinement of a minimal ERβ transcriptomic signature associated with response to ERβ-targeting agents, further informing the primary mechanisms through which ERβ elicits its tumor suppressive effects. Full article

Background: Breast cancer (BC) is the second most common cancer among women in the United States. It has been estimated that one in eight women will be diagnosed with breast cancer in her lifetime. Various BC risk factors, such as age, physical inactivity, and smoking, play a substantial role in BC occurrence and development. Early life dietary intervention with plant-based bioactive compounds has been studied for its potential role in BC prevention. Sulforaphane (SFN), an isothiocyanate, is an antioxidant and anti-inflammatory agent extracted from broccoli sprouts (BSp) and other plants. Dietary supplementation of SFN suppresses tumor growth by inducing protective epigenetic changes and inhibiting cancer cell proliferation. Inulin, as a dietary fiber, has been studied for alleviating GI discomfort and weight loss by promoting the growth of beneficial bacteria in the gut. Objective: Early-life combinatorial treatment with both phytochemical SFN and potential prebiotic agent inulin at lower and safer dosages may confer more efficacious and beneficial effects in BC prevention. Methods: Transgenic mice representing estrogen receptor-negative BC were fed 26% (w/w) BSp and 2% (w/v) inulin supplemented in food and water, respectively. Results: The combinatorial treatment inhibited tumor growth, increased tumor onset latency, and synergistically reduced tumor weight. Gut microbial composition was analyzed between groups, where Ruminococcus, Muribaculaceae, and Faecalibaculum significantly increased, while Blautia, Turicibacter, and Clostridium sensu stricto 1 significantly decreased in the combinatorial group compared with the control group. Furthermore, combinatorial treatment induced a protective epigenetic effect by inhibiting histone deacetylases (HDACs) and DNA methyltransferases (DNMTs). Intermediates in the AKT/PI3K/MTOR pathway were significantly suppressed by the combinatorial treatment, including PI3K p85, p-AKT, p-PI3K p55, MTOR, and NF-κB. Cell cycle arrest and programmed cell death were induced by the combinatorial treatment via elevating the expression of cleaved-caspase 3 and 7 and inhibiting the expressions of CDK2 and CDK4, respectively. Orally administering F. rodentium attenuated tumor growth and induced apoptosis in a syngeneic triple-negative breast cancer (TNBC) mouse model. Conclusions: Overall, the findings suggest that early-life dietary combinatorial treatment contributed to BC prevention and may be a potential epigenetic therapy that serves as an adjunct to other traditional neoadjuvant therapies. Full article

Background/Objectives:Cancer vaccine targets mostly include mutations and overexpressed proteins. However, cancer-associated post-translational modifications (PTMs) may also induce immune responses. Previously, our group established the enzyme protein arginine deiminase type-2 (PADI2), which catalyzes citrullination modification, is highly expressed in triple-negative breast cancer (TNBC), promoting antigenicity. Methods: Here, we show the workflow of designing citrullinated enolase 1 (citENO1) vaccine peptides identified from breast cancer cells by mass spectrometry and demonstrate TNBC vaccine efficacy in the mouse model. Immunized mice with citENO1 peptides or the corresponding unmodified peptides, plus Poly I:C as an adjuvant, were orthotopically implanted with a TNBC murine cell line. Results: Vaccination with citENO1, but not unmodified ENO1 (umENO1), induced a greater percentage of activated CD8+ PD-1+ T cells and effector memory T cells in skin-draining lymph nodes (SDLNs). Remarkably, the citENO1 vaccine delayed tumor growth and prolonged overall survival, which was further enhanced by PD-1 blockade. Conclusions: Our data suggest that cancer-restricted post-translational modifications provide a source of vaccines that induce an anti-cancer immune response. Full article

Breast cancer is a major global health burden with the highest incidence in women, and triple-negative breast cancer (TNBC) stands out as the most malignant subtype. Effective therapeutic targets are urgently needed to develop new therapies for TNBC. Nicotinic acetylcholine receptor is a ligand-gated ion channel receptor that is associated with the advancement of multiple cancers. Notably, α9 nicotinic acetylcholine receptor (α9 nAChR) is less investigated towards its role in cancer. This study sought to clarify the significance of α9 nAChR in TNBC. Firstly, our results uncovered that the expression of CHRNA9 was notably elevated in TNBC tissues and was associated with poor prognosis of TNBC patients. Further, our data indicated that overexpression of α9 nAChR facilitated the growth of TNBC cells, via mechanisms of simultaneously activating AKT-, ERK- and STAT3-mediated proliferation and negatively regulating ferroptosis through promoting SLC7A11/GSH/GPX4 and Keap1/Nrf2/HO1 signaling. Conversely, CHRNA9 knockdown would completely reverse all this signaling, ultimately inhibiting TNBC tumor growth both in vitro and in vivo. Finally, we reported a specific polypeptide antagonist of α9 nAChR, GeXIVA[1,2] and exerted good anti-tumor effects in tumor-bearing mice of TNBC, which indicated a great potential of GeXIVA[1,2] to be further studied as a novel targeted therapy for TNBC. This study provides a scientific basis for establishing α9 nAChR as a novel therapeutic target for TNBC, which is worthy of further development in the future. Full article

Although thymoquinone (TQ) has been reported as an anti-tumor small molecule well investigated in numerous tumors. In this study, we designed and synthesized a novel TQ derivative, TQFL28, with a molecular formula of C₂₀H₂₃NO₂. TQFL28 showed stronger cytotoxicity or anti-proliferative activities against triple-negative breast cancer (TNBC) cell lines (BT549, MDA-MB-231, or 4T1) than TQ but is lower in the normal mammary epithelial cells, MCF10A. TQFL28 exhibited lower IC₅₀ values toward BT549 (38.78 ± 1.589) and MDA-MB-231 (39.63 ± 1.598) cells compared to TQ, indicating its efficacy for TNBC cytotoxicity. TQFL28 inhibited the growth, migration, and invasiveness of TNBC cells of 4T1 and BT549 in vitro and tumor progression and metastasis in a 4T1 allograft animal model in vivo. Moreover, TQFL28 presents lower toxicity than TQ in mice, showing a 7-day half-lethal dose (LD₅₀) of 59.43 mg/kg (41.6–83.6, 95% confidence interval). Altogether, our study obtained. In addition, TQFL28 induced a significant reduction in tumor volumes in the mouse model in comparison to the vehicle group. TQFL28, a novel small molecule, has a superior inhibitory effect and lower toxicity on TNBC both in vitro and in vivo. Thus, TQFL28 might have potential as a therapeutic small molecule for breast cancer, especially in TNBC. Full article

Triple-negative breast cancer (TNBC), characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor type 2 (HER2) expression, represents a therapeutic challenge due to its aggressive nature and limited treatment options. Here, we identified the cholesterol-lowering drug lovastatin (LV) as a potent apoptosis-inducing agent in TNBC. Mechanistically, LV disrupts the interaction between the deubiquitinating enzyme USP14 and Survivin, a key anti-apoptotic protein, enhancing polyubiquitination and the proteasomal degradation of Survivin. The overexpression of USP14 was found to stabilize Survivin and rescue LV-induced apoptosis and tumor suppression in vitro and in vivo, whereas USP14 silencing or inhibition with IU1 (a USP14-specific inhibitor) enhanced Survivin turnover and synergized with LV to suppress colony formation in TNBC cells. Clinical relevance was demonstrated through bioinformatic analysis and immunohistochemistry, revealing that elevated Survivin expression in TNBC tissues correlated with poor prognosis and is significantly upregulated in TNBC versus non-TNBC tissues. Our findings identify the USP14–Survivin axis as a potential therapeutic target and highlight LV as a promising candidate for TNBC treatment. Full article

Triple-negative breast cancer (TNBC) is an aggressive cancer characterized by a high risk of recurrence, invasiveness, metastatic potential, and poor prognosis. Tumor-associated macrophages (TAMs), particularly M2-like TAMs, contribute to TNBC progression by promoting an immunosuppressive tumor microenvironment (TME), highlighting the need for TME remodeling. This study aimed to evaluate the therapeutic efficacy of co-administering CL7, a CD300c monoclonal antibody that induces M1 macrophage polarization, and anti-PD-1, an immune checkpoint inhibitor, in TNBC. To establish a TNBC model, 4T1 cells were inoculated into the fourth left mammary gland of mice. CL7 and anti-PD-1 were intravenously administered twice a week. Flow cytometry and RT-PCR were performed to assess the immunotherapeutic effects, and lung metastases were evaluated by the Hematoxylin and Eosin staining of lung tissues. Tumor growth was significantly reduced in the combination treatment group (CL7 and anti-PD-1) compared to both the PBS and monotherapy groups. Additionally, the combination treatment increased M1 macrophages and activated CD8+ T and NK cells in the tumor, while significantly suppressing lung metastases. These findings suggest that the combination of CL7 and anti-PD- therapy has the potential to treat TNBC by remodeling the TME. Full article

Background: The anti-tumor response of the immune system is pivotal for treating triple-negative breast cancer (TNBC), particularly as targeted therapies are limited. However, the impact of immune-modulating factors such as the application of granulocyte-stimulating factors (G-CSFs) or infections, including febrile neutropenia, prophylactic or therapeutical application of oral antibiotics (OABs), and the need for intravenous antibiotics (IABs), on survival outcomes remains unclear. Methods: 1583 patients with early-stage TNBC enrolled in the SUCCESS A or C study underwent primary surgery, adjuvant chemotherapy, and radiotherapy if indicated. All patients had Eastern Cooperative Oncology Group (ECOG) status ≤ 2. The effects of G-CSF, OAB, and IAB application on overall survival (OS), invasive disease-free survival (iDFS), breast cancer-specific survival (BCSS), and distant disease-free survival (DDFS) were assessed. Results: Only IAB treatment was significantly associated with decreased survival in univariable analyses (OS: p = 0.003; iDFS: p = 0.036; BCSS: p = 0.011; DDFS: p = 0.044), while G-CSF and OAB administration were not. Adjusted multivariable Cox regressions including febrile neutropenia and dose reduction/shift, ECOG, age of patients, and other clinicopathological parameters confirmed a significant negative effect of IABs on OS (p = 0.020), BCSS (p = 0.018), and DDFS (p = 0.044). Conclusions: In summary, IABs during adjuvant chemotherapy seems to be a risk factor for inferior OS, BCSS, and DDFS in TNBC patients, possibly by affecting microbiome-related immune response modulation. Hence, preventive measures to avoid the need for IABs should be considered in these patients. Full article