Triple-negative Breast Cancer Research Articles

Clinical Significance of FAM83G in Breast Cancer: Association With Triple-negative Subtype and Prognosis.

Family with sequence similarity 83 member G (FAM83G) plays an important role in cancer aggressiveness and patients' prognosis across various types of cancer. However, the association of FAM83G protein expression in breast cancer with clinicopathologic factors, breast cancer subtypes, and prognosis is not well characterized. This study aimed to elucidate the clinical significance of FAM83G protein expression in breast cancer. Immunohistochemistry was employed to examine FAM83G protein expression in 75 breast cancer tissues, assessing its potential as a biomarker for breast cancer patients. The Kaplan-Meier plotter was used to estimate the correlation between FAM83G mRNA expression and survival outcomes in TNBC patients. FAM83G protein was predominantly localized in the cytoplasm of breast cancer cells, exhibiting uniform expression throughout tumor tissues. FAM83G expression was significantly higher in cancerous areas compared to non-cancerous areas. High FAM83G expression was more prevalent in triple-negative breast cancer (TNBC) cases than in hormone receptor-positive cases. Although high FAM83G protein expression did not significantly impact prognosis in our cohort, a large-scale database analysis revealed an association between high FAM83G expression and poor prognosis in TNBC cases. This study demonstrates an association between high FAM83G expression in breast cancer tissues and TNBC. FAM83G may serve as a promising biomarker and therapeutic target for breast cancer patients.

Comparison of the Predictive and Prognostic Capacities of Neutrophil, Lymphocyte and Platelet Counts and Tumor-infiltrating Lymphocytes in Triple-negative Breast Cancer: Preliminary Results of the PERCEPTION Study.

Triple-negative breast cancer (TNBC) is the most heterogeneous breast cancer subtype, posing numerous challenges in clinical decision-making. Biomarkers are essential to personalize management of TNBC patients. While tumor infiltrating lymphocytes (TILs) are validated prognostic biomarkers, the requirement for tumor biopsy limits their routine use. Therefore, more accessible and reliable quantitative biomarkers are needed. Given the significant role of systemic inflammatory response in tumor onset and progression, assessing inflammatory cells via liquid biopsies emerges as a promising alternative. The PERCEPTION study, conducted at Centre Jean Perrin in France, aims to determine the correlation between TILs and peripheral blood components at diagnosis. An interim analysis was conducted after enrolling 50% of the estimated population, to evaluate study feasibility and preliminary correlations between blood cell counts and TILs. Sixty-one patients were enrolled over 4.5 years, demonstrating a good inclusion rate with minimal missing data. Preliminary results for 36 analyzable patients showed no correlation between the neutrophil-to-lymphocyte ratio (NLR) and TILs (rs=-0.19, 95%CI=-0.49-0.16, p=0.3). However, a moderate, positive, statistically significant correlation was found between NLR and the CD8/FoxP3 TILs ratio (rs=0.36, 95%CI=0.03-0.64, p=0.043). The probabilistic index of 0.7 (p=0.06) between NLR-high and NLR-low groups for this ratio supports the correlation. The interim analysis of the PERCEPTION study confirms the feasibility of correlating blood cell counts with TILs in TNBC. Although no significant correlation was observed between NLR and TILs, the moderate positive correlation between the CD8/FoxP3 ratio and TILs suggests a potential link between systemic inflammation and local immune response. These findings underscore the potential of blood-based markers as non-invasive surrogates for TILs, encouraging further research to enhance prognosis and guide treatment strategies in TNBC.

Spatial Architecture of Single-cell and Vasculature in Tumor Microenvironment Predicts Clinical Outcomes in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited treatment options, which warrants the identification of novel therapeutic targets. Deciphering nuances in the tumor microenvironment (TME) may unveil insightful links between anti-tumor immunity and clinical outcomes, yet such connections remain underexplored. Here we employed a dataset derived from imaging mass cytometry of 71 TNBC patient specimens at single-cell resolution and performed in-depth quantifications with a suite of multi-scale computational algorithms. The TNBC TME reflected a heterogeneous ecosystem with high spatial and compositional heterogeneity. Spatial analysis identified ten recurrent cellular neighborhoods (CNs) – a collection of local TME characteristics with unique cell components. The prevalence of CNs enriched with B cells, fibroblasts, and tumor cells, in conjunction with vascular density and perivasculature immune profiles, could significantly enrich for long-term survivors. Furthermore, relative spatial colocalization of SMAhi fibroblasts and tumor cells compared to B cells correlated significantly with favorable clinical outcomes. Using a deep learning model trained on engineered spatial data, we can predict with high accuracy (mean AUC of 5-fold cross-validation = 0.71) how a separate cohort of patients in the NeoTRIP clinical trial will respond to treatment based on baseline TME features. These data reinforce that the TME architecture is structured in cellular compositions, spatial organizations, vasculature biology, and molecular profiles, and suggest novel imaging-based biomarkers for treatment development in the context of TNBC.

A study of the role of androgen receptor and androgen receptor variant 7 in TNBC patients and the effect of their targeting by Enzalutamide and EPI-001 in MDA-MB-231

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.

Synthesis, anticancer activity and mechanism of action of Fe(III) complexes.

To inhibit the growth and metastasis of triple-negative breast cancer (TNBC), two Fe(III) thiosemicarbazone complexes (Fe1 and Fe2) were designed and synthesized. The structures of the Fe(III) complexes were characterized by single crystal X-ray diffraction. The antiproliferative activity of Fe1 and Fe2 against four cancer lines (MDA-MB-231, T98G, HepG2, 143B) and human renal proximal tubular epithelial cell line (HK-2) was evaluated by MTT assay. Among all cells, Fe2 showed significant cytotoxicity to TNBC cells (MDA-MB-231), with an IC50 value of 12.38 μM. Furthermore, Fe2 showed less toxicity to HK-2 cells. The two Fe(III) complexes can produce excess of reactive oxygen species, decrease of mitochondrial membrane potential, and induce DNA damage, then lead to apoptosis of MDA-MB-231 cells. In addition, Fe1 and Fe2 can also inhibit migration and invasion of MDA-MB-231 cells. This study provides guidance for the development of metal complexes that inhibit the growth and metastasis of TNBC.

Inhibition of Notch enhances efficacy of immune checkpoint blockade in triple-negative breast cancer.

Aberrant Notch, which is a defining feature of triple-negative breast cancer (TNBC) cells, regulates intercellular communication in the tumor immune microenvironment (TIME). This includes tumor-associated macrophage (TAM) recruitment through Notch-dependent cytokine secretion, contributing to an immunosuppressive TIME. Despite the low response rate of TNBC to immune checkpoint blockade (ICB), here, we report that inhibition of Notch-driven cytokine-mediated programs reduces TAMs and induces responsiveness to sequentially delivered ICB. This is characterized by the emergence of GrB+ cytotoxic T lymphocytes (CTLs) in the primary tumor. A more impressive effect of sequential treatment is observed in the lung where TAM depletion and increased CTLs are accompanied by near-complete abolition of metastases. This is due to (i) therapeutic reduction in Notch-dependent, prometastatic circulating factors released by the primary tumor, and (ii) elevated PD ligand 1 (PD-L1) in lung metastases, rendering them profoundly sensitive to ICB. These findings highlight the potential of combination cytokine inhibition and ICB as an immunotherapeutic strategy in TNBC.

89Zr-Labeled DFO@Durvalumab-HSA nanoparticles: In vitro potential for triple-negative breast cancer.

This study presents the development and evaluation of a DFO@mAb-NP (DFO@Durvalumab-HSA-DTX nanoparticle) nanoplatform for imaging in triple-negative breast cancer (TNBC). The nanoplatform demonstrated significant changes postconjugation with DFO, evidenced by increased particle size from 178.1 ± 5 nm to 311 ± 26 nm and zeta potential alteration from -31.9 ± 3 mV to -40.5 ± 0.8 mV. Fourier-transform infrared spectroscopy and ultraviolet spectral analyses confirmed successful DFO conjugation, with notable shifts in peak wavelengths. High labeling efficiency was achieved with 89Zr, as indicated by thin layer radio chromatography and high-performance liquid radio chromatography results, with labeling efficiencies of 98 ± 2% for 89Zr-DFO@mAb and 96 ± 3% for 89Zr-DFO@mAb-NP. The nanoplatforms maintained stability over 24 h, showing less than 5% degradation. Lipophilicity assays revealed logP values of 0.5 ± 0.03 for 89Zr-DFO@mAb-NP and 0.98 ± 0.2 for 89Zr-DFO@mAb, indicating a higher lipophilic tendency in the radiolabeled Durvalumab. Cell uptake experiments showed an initial high uptake in MDA-MB-468 cells (45.1 ± 3.2%), which decreased over time, highlighting receptor-specific interactions. These comprehensive findings suggest the promising potential of the DFO@mAb-NP nanoplatform for targeted imaging in TNBC, with implications for improved diagnostic accuracy and treatment strategies.

CD47 and Calreticulin Expression in Breast Cancer Subtypes and Anti-CD47 Inhibitory Effects in Macrophage-mediated Phagocytosis.

Macrophage-mediated cancer immune evasion is modulated by the balance between "the cluster of differentiation 47 (CD47), an anti-phagocytic signal" and "calreticulin (CALR), a pro-phagocytic signal". CD47 is highly expressed in various types of cancer. However, the expression profiles of CD47 and CALR in breast cancer, especially in different hormone receptor subtypes, and the effects of CD47 blockade in macrophage-mediated therapy are not well understood. The expression levels of CD47 and CALR were investigated in breast cancer and adjacent normal tissues using immunohistochemistry. To study the effects of CD47 blockade therapy, CD47 and CALR expression in breast cancer cell lines were determined. In vitro macrophage-mediated phagocytosis of breast cancer upon treatment with a monoclonal CD47 antibody (B6H12) were performed. CD47 and CALR were overexpressed in breast cancer tissues and their up-regulation was associated with hormone receptor subtypes. Patients with Luminal A breast cancer had higher levels of CD47, while patients with triple-negative breast cancer (TNBC) had higher levels of CALR. The levels of CD47 and CALR were also elevated in breast cancer cell lines of Luminal A (MCF-7) and TNBC (MDA-MB-231) subtypes. Interestingly, the expression ratio of surface CD47/CALR was significantly higher in MCF-7. Moreover, in vitro phagocytosis assays revealed that blockage of CD47 enhanced macrophage-mediated activity in both cancer cells with dramatically higher degrees of phagocytosis in MCF-7. The expression profiles of CD47 and CALR in breast cancer subtypes and the benefit of CD47 blocking-based immunotherapy are herein provided.

AXL/GAS6 signaling governs differentiation of tumor-associated macrophages in breast cancer

Most epithelial cancers are infiltrated by prognostically relevant myelomonocytic cells. Immunosuppressive tumor associated macrophages (TAMs) and their precursor monocytic-MDSCs have previously been associated with worse outcomes in human breast cancer (BCa), yet the mechanism of immunosuppressive TAMs-polarization from myelomonocytic precursors is not completely understood. In this study, we show that persuaded AXL/GAS6 pathway alters macrophage phenotype from HLA-DRhighCD206low CD163low classical phagocytic into HLA-DRlowCD206highCD163high immunosuppressive ones with accelerated BCa progression, and increased angiogenesis signature and invasion ability of cancer cells at tumor beds. Notably, both AXL and GAS6 expressions are upregulated in human invasive breast carcinoma, with maximum expression in triple negative histology type. Mechanistically, we demonstrate that AXL/GAS6 signaling drives immunosuppression by governing increased immunosuppressive IL10 production while dampening IL-1β expression within the tumor microenvironment (TME) of BCa. Further, AXL/GAS6 signaling promotes angiogenesis through the activation of PI3K/AKT and NF-κB signaling pathways. Our results unveil role of AXL/GAS6 axis in the differentiation of TAMs, which governs malignant growth, and suggest that therapies that uncouple AXL/GAS6 axis may exhibit therapeutic opportunity for otherwise undruggable Triple Negative Breast Cancer (TNBC) patients.

Synthesis of cotton-like FeCoNi-Nd(OH)3 nanoparticles via reactive mechanical milling: Investigating chemical properties for cellular signaling applications

In this study, FeCoNi alloy nanoparticles were combined with Nd(OH)3 nanostructures to create unique cotton-like nanoparticles (C-NPs). These C-NPs were synthesized through an accessible, two-step reactive chemical milling process. The nanoparticles originated from a blend of metal chlorides (FeCl2, CoCl2, and NiCl2) and sodium (Na), used as a precursor in the reaction, within a SPEX milling apparatus. The Fe, Co, and Ni were maintained at equal weight percentages (1:1:1). Subsequently, NdCl3 and Na were utilized to facilitate the attachment of Nd(OH)3 nanostructures onto the FeCoNi nanoparticles through a solid-state reaction in the same SPEX milling setup. The Nd content was varied to investigate its effect on the integration of Nd(OH)3 onto the surface of CoNiFe nanoparticles. Electron microscopy revealed the formation of cotton-like nanoparticles, and the distribution of elements was identified using secondary ion mass spectrometry. The CoNiFe alloy and Nd(OH)3 phases were verified by X-ray diffraction analysis. These nanoparticles were internalized into cells via endocytosis, as observed in transmission electron microscopy images after incubation with the BT20 cell line (triple-negative breast cancer), likely due to interactions between –OH groups and the cell membrane. Following this, the cells containing C-NPs underwent photoluminescence studies, revealing two distinct emission peaks at 400 nm, and 486 nm. X-ray photoelectron spectroscopy indicated the presence of various heterostructures within the FeCoNi-Nd(OH)3 complex, which may be responsible for these emission properties.

Tetrahydrocurcumin targets TRIP13 inhibiting the interaction of TRIP13/USP7/c-FLIP to mediate c-FLIP ubiquitination in triple-negative breast cancer

IntroductionTriple-negative breast cancer (TNBC) has a high mortality rate and limited treatment options. Tetrahydrocurcumin (THC), a major metabolite of curcumin, has potential antitumor activities. However, the antitumor effects and mechanism of THC in TNBC remain elusive. ObjectivesTo investigate the mechanism of THC in combating TNBC by targeting TRIP13 to disrupt the interaction of the TRIP13/USP7/c-FLIP complex and mediate c-FLIP ubiquitination both in vitro and in vivo. MethodsApoptosis was measured by TUNEL and flow cytometry. Click chemistry-based target fishing, CETSA, DARTS, and SPR were used to identify direct target of THC. Protein interactions was examined using co-immunoprecipitation. The role of USP7 in THC-mediated c-FLIP ubiquitination was evaluated by in vitro deubiquitination assay. Human breast cancer clinical samples were employed to assess the expression of c-FLIP, TRIP13, and USP7. The impact of THC on USP7/TRIP13/c-FLIP was analyzed using co-immunoprecipitation, confocal microscopy, molecular docking and dynamics simulations. ResultsTHC effectively inhibits TNBC cell proliferation and tumor growth in vitro and in vivo without significant toxicity. Mechanistically, THC induces extrinsic apoptosis in TNBC primarily by promoting degradation of c-FLIP, a key negative regulator in the apoptotic pathway. Furthermore, utilizing click chemistry-based target fishing, we identified TRIP13, a component of the highly conserved AAA ATPase family, as a direct target of THC in combating TNBC. Interestingly, contrary to previous drug-target studies, the knockdown of TRIP13 further amplified the antitumor effects of THC. After in-depth investigation, it was revealed that TRIP13 forms a trimeric complex with USP7 and c-FLIP in TNBC cells. THC specifically targets TRIP13 to disrupt the interaction of TRIP13/USP7/c-FLIP, leading to the ubiquitination of c-FLIP, ultimately inducing extrinsic apoptosis. ConclusionsThese findings offer new insights into the novel molecular mechanisms of anti-TNBC effects of THC and present a promising targeted therapeutic strategy for TNBC.

Immunosuppressive SOX9-AS1 Resists Triple-Negative Breast Cancer Senescence Via Regulating Wnt Signalling Pathway.

Long noncoding RNAs (lncRNAs) are involved in the regulation of triple-negative breast cancer (TNBC) senescence, while pro-carcinogenic lncRNAs resist senescence onset leading to the failure of therapy-induced senescence (TIS) strategy, urgently identifying the key senescence-related lncRNAs (SRlncRNAs). We mined seven SRlncRNAs (SOX9-AS1, LINC01152, AC005152.3, RP11-161 M6.2, RP5-968 J1.1, RP11-351 J23.1 and RP11-666A20.3) by bioinformatics, of which SOX9-AS1 was reported to be pro-carcinogenic. Invitro experiments revealed the highest expression of SOX9-AS1 in MDA-MD-231 cells. SOX9-AS1 knockdown inhibited cell growth (proliferation, cycle and apoptosis) and malignant phenotypes (migration and invasion), while SOX9-AS1 overexpression rescued these effects. Additionally, SOX9-AS1 knockdown facilitated tamoxifen-induced cellular senescence and the transcription of senescence-associated secretory phenotype (SASP) factors (IL-1α, IL-1β, IL-6 and IL-8) mechanistically by resisting senescence-induced Wnt signal (GSK-3β/β-catenin) activation. Immune infiltration analysis revealed that low SOX9-AS1 expression was accompanied by a high infiltration of naïve B cells, CD8+ T cells and γδ T cells. In conclusion, SOX9-AS1 resists TNBC senescence via regulating the Wnt signalling pathway and inhibits immune infiltration. Targeted inhibition of SOX9-AS1 enhances SASP and thus mobilises immune infiltration to adjunct TIS strategy.

Protein arginine methyltransferase 5 confers the resistance of triple-negative breast cancer to nanoparticle albumin-bound paclitaxel by enhancing autophagy through the dimethylation of ULK1

Chemotherapy remains the major strategy for treating triple-negative breast cancer (TNBC); however, frequently acquired chemoresistance greatly limits the treatment outcomes. Protein arginine methyltransferase 5 (PRMT5), which modulates arginine methylation, is important in chemoresistance acquisition across various cancers. The function of PRMT5 in the development of chemoresistance in TNBC is still not well understood. This work focused on defining PRMT5's function in contributing to the chemoresistance in TNBC and demonstrating the possible mechanisms involved. Two TNBC cell lines resistant to nanoparticle albumin-bound paclitaxel (Nab-PTX), designated MDA-MB-231/R and MDA-MB-468/R, were developed. The expression of PRMT5 was markedly elevated in the cytoplasm of Nab-PTX-resistant cells accompanied with enhanced autophagy. The depletion of PRMT5 rendered these cells sensitive to Nab-PTX-evoked cytotoxicity. The autophagic flux was upregulated in Nab-PTX-resistant cells, which was markedly repressed by PRMT5 depletion. The dimethylation of ULK1 was markedly elevated in Nab-PTX-resistant cells, which was decreased by silencing PRMT5. Re-expression of PRMT5 in PRMT5-depleted cells restored the dimethylation and activation of ULK1 as well as the autophagic flux, while the catalytically-dead PRMT5 (R368A) mutant showed no significant effects. The depletion of PRMT5 rendered the subcutaneous tumors formed by Nab-PTX-resistant TNBC cells sensitive to Nab-PTX. The findings of this work illustrate that PRMT5 confers chemoresistance of TNBC by enhancing autophagy through dimethylation and the activation of ULK1, revealing a novel mechanism for understanding the acquisition of chemoresistance in TNBC. Targeting PRMT5 could be a viable approach for overcoming chemoresistance in the treatment of TNBC.

Correlation of safety and efficacy of atezolizumab therapy across indications

BackgroundThe association between safety and efficacy of immune checkpoint inhibitors is known, but the correlation between severity and impact of specific organ involvement by immune-related adverse events (irAE) and cancer...

Integrated stress response-upregulated mitochondrial SLC1A5var enhances glucose dependency in human breast cancer cells in vitro

Breast cancer is the most commonly diagnosed cancer among women. The growth of triple-negative breast cancer (TNBC) cells is glucose-dependent. The integrated stress response (ISR) is a cellular stress response to glucose depletion. The ISR-solute carrier family 7 member 11 pathway is activated during glucose depletion and contributes to glucose dependence by decreasing intracellular glutamate levels. Solute carrier family 1 member 5 (SLC1A5) and the mitochondrial solute carrier family 1 member 5 variant (SLC1A5var) are glutamine transporters that play essential roles in the reprogramming of cancer metabolism. However, whether ISR can regulate mitochondrial SLC1A5var expression and further affect glucose dependence remains unclear. Glucose depletion-, oligomycin-, and salubrinal-activated activating transcription factor-4 (ATF4) induced SLC1A5var expression. ATF4 is critical for SLC1A5var regulation, as it binds to specific regulatory elements in its promoter. SLC1A5var knockdown decreases glucose depletion-induced cell death, whereas SLC1A5var overexpression increases glucose depletion-induced cell death in TNBC cells. SLC1A5var knockdown reduced cancer cell proliferation, colony formation, and migration, whereas SLC1A5var overexpression increased cell proliferation and migration. Moreover, the knockdown of SLC1A5var reduces the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) while increasing the maximal OCR and ECAR under glucose depletion. These results suggest that activated ISR-induced increased expression of SLC1A5var may regulate mitochondrial oxidative phosphorylation and glycolytic metabolic characteristics to enhance glucose depletion-induced cell death. In conclusion, SLC1A5var plays a vital role in metabolic reprogramming and may be a potential target for breast cancer treatment.

Proton pump inhibitor attenutes acidic microenvironment to improve the therapeutic effects of MSLN-CAR-T cells on the brain metastasis of solid tumors

The incidence of brain metastasis (BM) is gradually increasing, and the prognosis and therapeutic effect are poor. The emergence of immunotherapy has brought hope for the development of BM treatments. This study revealed that compared with primary cancers (PCs), BMs have a “colder” and more acidic tumor microenvironment (TME), resulting in reduced protein levels of mesothelin (MSLN), a promising target for chimeric antigen receptor-T (CAR-T) cell therapy for triple-negative breast cancer (TNBC) with BMs. These factors could significantly decrease the efficiency of MSLN-CAR-T cells in TNBC BMs. Pantoprazole (PPZ) administration at the most commonly used dose in the clinic notably increased the pondus hydrogenii (pH) of the TME, inhibited lysosomal activity, increased the membrane levels of the MSLN protein and improved the killing ability of MSLN-CAR-T cells both in vitro and in vivo. Similar results were obtained in non-small cell lung cancer (NSCLC) BMs. Hence, when administered in combination with CAR-T cells, PPZ, which increases the protein levels of target antigens, may constitute a new immunotherapeutic strategy for treating solid tumors with BMs.

Development of targeted lipid nanoparticles for the combined therapy of triple negative breast cancer: can curcumin and 6-aminoflavone promote doxorubicin in vitro efficacy?

Development of targeted lipid nanoparticles for the combined therapy of triple negative breast cancer: can curcumin and 6-aminoflavone promote doxorubicin in vitro efficacy?

DNA-templated nanosheets for enhanced chemodynamic therapy and gene therapy to inhibit tumor recurrence and metastasis

Recurrence and metastasis stand as the primary contributors to mortality among patients with triple-negative breast cancer post-surgery, presenting a formidable clinical obstacle. Chemodynamic therapy (CDT), leveraging metal-ion-mediated Fenton-like reactions within the tumor microenvironment (TME), emerges as a promising avenue for addressing cancer metastasis. Despite recent progress, challenges such as tumor cell antioxidant defenses and epithelial-mesenchymal transition (EMT) impede the efficacy of CDT. Here, we introduce a novel approach using DNA-templated nanosheets (Dz-MnO2) that combine the functions of Mn2+-mediated CDT and DNAzyme-mediated gene therapy to suppress tumor growth and metastasis. The Dz-MnO2 nanosheets respond effectively to the TME, releasing Mn2+ and DNAzyme. The DNAzyme exhibits mRNA cleavage activity, specifically targeting oncogenic transcripts to reduce tumor progression. Mn2+ not only facilitates a Fenton-like reaction, enhancing the chemodynamic treatment effect, but also serves as a cofactor for DNAzyme, improving its catalytic efficiency. Concurrently, the nanosheets robustly silence the Twist1 gene, mitigating the EMT process and reinforcing CDT efficacy by suppressing apoptosis resistance. Results indicate that Dz-MnO2 nanosheets efficiently polarize M2-tumor-associated macrophages (TAMs) into M1-TAMs by locally mitigating tumor hypoxia via catalyzing the decomposition of H2O2 into O2. This collaborative strategy presents a promising approach to enhance CDT, effectively inhibiting tumor recurrence and metastasis.

Combining ultrasound technology with targeted fucoidan/arginine-gelatin nanoparticles loaded with doxorubicin to enhance therapeutic efficacy and modulate bioeffects in drug-resistant triple-negative breast cancer

Combining ultrasound technology with targeted fucoidan/arginine-gelatin nanoparticles loaded with doxorubicin to enhance therapeutic efficacy and modulate bioeffects in drug-resistant triple-negative breast cancer

Phytosesquiterpene Lactones Deregulate Mitochondrial Activity and Phenotypes Associated with Triple-Negative Breast Cancer Metastasis

Phytosesquiterpene Lactones Deregulate Mitochondrial Activity and Phenotypes Associated with Triple-Negative Breast Cancer Metastasis