Therapy For Triple-negative Breast Cancer Research Articles

SHP2 promotes the epithelial-mesenchymal transition in triple negative breast cancer cells by regulating β-catenin.

Growing evidence suggests that the tyrosine phosphatase SHP2 is pivotal for tumor progression. Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer, characterized by its high recurrence rate, aggressive metastasis, and resistance to chemotherapy. Understanding the mechanisms of tumorigenesis and the underlying molecular pathways in TNBC could aid in identifying new therapeutic targets. In this study, we conducted bioinformatics analysis of the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases to examine PTPN11 (encoding SHP2) expression levels and perform survival analysis in TNBC. Additionally, we analyzed SHP2 levels in four TNBC cell lines and a normal breast epithelial cell line using Western blot. Furthermore, we knocked down SHP2 expression via RNA interference in three TNBC cell lines. To assess the impact of SHP2 on invasion and migration, we conducted transwell assays and wound healing experiments. An in vivo experiment utilizing a mouse xenograft model was also performed to evaluate tumor metastasis. Moreover, we detected the expression levels of epithelial-mesenchymal transition (EMT) biomarkers and investigated the mechanism between SHP2 and β-catenin using Western blot and immunofluorescence experiments. We found that high SHP2 expression was associated with a poor prognosis in patients with TNBC. The migratory and invasive abilities of TNBC cells in vitro, as well as the metastatic potential of TNBC in mouse xenograft models, were reduced after SHP2 depletion. Downregulation of SHP2 also decreased the expression of mesenchymal markers but induced upregulation of the epithelial marker E-cadherin. Additionally, SHP2 promoted β-catenin stability by inhibiting its degradation via the proteasome. Furthermore, c-Myc expression and GSK3β and AKT phosphorylation, which are involved in β-catenin signaling, were decreased in SHP2-depleted TNBC cells. Our study demonstrates that SHP2 is involved in migration, invasion, and EMT in TNBC cells by modulating β-catenin. Manipulating SHP2 expression or its target protein β-catenin may offer a novel approach to TNBC therapy.

In situ generation of Copper sulfide within Poly(lactic-co-glycolic acid): A strategy for Safer photothermal therapy in Triple-Negative breast cancer.

Copper sulfide nanoparticles (CuS NPs) have garnered significant attention in photothermal therapy (PTT) owing to their facile synthesis, biodegradability, stability, and excellent photothermal conversion efficiency. Nonetheless, their potential toxic effects have restricted their application. This research focuses on the encapsulation of CuS NPs with the biocompatible polymer poly(lactic-co-glycolic acid) (PLGA) to enhance their biocompatibility, thereby improving the efficacy and safety of PTT in the treatment of triple-negative breast cancer (TNBC). Three distinct methods, namely aqueous phase loading method, oil phase loading method, and "in situ reduction" method were employed to synthesize PLGA-coated CuS (CuS@PLGA) NPs to optimize the encapsulation rate of CuS. Among these, the CuS@PLGA NPs fabricated via the "in situ reduction" method demonstrated the highest encapsulation efficiency for CuS, achieving a rate of (90.4 ± 3.3)%. The resulting CuS@PLGA NPs exhibited high stability, excellent photothermal effect, and good tumor-targeting ability. Moreover, CuS@PLGA NPs demonstrated enhanced anti-tumor efficacy and biocompatibility compared to CuS NPs in both in vitro and in vivo experiments. Consequently, this study offers an effective and safety strategy for PTT treatment of TNBC.

Targeting NANOS1 in triple-negative breast cancer: synergistic effects of digoxin and PD-1 inhibitors in modulating the tumor immune microenvironment

IntroductionTriple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer resistant to endocrine and targeted therapies. Immune checkpoint inhibitors (ICIs) have shown significant efficacy in various cancers. Taraxacum officinale, commonly known as dandelion, has traditionally been used to treat breast-related diseases and is recognized for its beneficial composition and low side effects. FDA-approved drugs, having undergone rigorous validation for their safety, efficacy, and quality, provide a foundation for drug repurposing research. Researchers may explore FDA-approved drugs targeting the potential target NANOS1 for TOE (Taraxacum officinale extract) treatment to develop innovative therapeutic strategies. In this context, Dig (Digoxin) and AA (Algestone acetophenide) have been identified as potential drug candidates for further exploration of their therapeutic effects and application potential in targeting NANOS1.MethodsRNA sequencing (RNA-seq) was employed to identify potential targets for triple-negative breast cancer (TNBC) from TOE. Bioinformatics tools, including bc-GenExMiner v4.8, the Human Protein Atlas, and the TIMER database, were utilized for target identification. Molecular docking studies assessed FDA-approved drugs interacting with these targets, with Dig and AA selected as candidate drugs. The therapeutic efficacy of Dig and AA in combination with PD-1 inhibitors was evaluated using the 4T1 mouse model. Flow cytometry was applied to assess lymphocyte infiltration in the tumor immune microenvironment. RNA-seq analysis after target silencing by small interfering RNA (siRNA) was performed, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Validation of findings was conducted through quantitative PCR and Western blot analysis.ResultsTOE inhibited TNBC cell growth, migration, and invasion, as assessed by CCK-8 and transwell assays. RNA-seq indicated the effects may be due to NANOS1 down-regulation. Survival analysis showed lower NANOS1 expression correlated with better prognosis. Immunoinfiltration analysis indicated a negative correlation between NANOS1 levels and activated NK cells. Molecular docking identified Dig and AA as high-affinity binders of NANOS1. Animal experiments showed Dig and PD-1 inhibitor combination enhanced immunotherapy efficacy for TNBC.DiscussionThe findings from this study suggest that TOE may offer a novel therapeutic approach for TNBC by targeting NANOS1, a protein whose down-regulation is associated with improved patient outcomes. The negative correlation between NANOS1 and activated NK cells highlights the potential role of the immune system in TNBC pathogenesis and response to treatment. The identification of Dig as potential drugs targeting NANOS1 provides a new direction for drug repurposing in TNBC. The synergistic effect of Dig and PD-1 inhibition observed in animal models is promising and warrants further investigation into the role of immunotherapy in TNBC treatment. Overall, this study identifies NANOS1 as a new target for TNBC therapy and suggests a combination therapy approach that could enhance immunotherapy effectiveness and improve patient outcomes.

Secernin-2 Stabilizes Histone Methyltransferase KMT2C to Suppress Progression and Confer Therapeutic Sensitivity to PARP Inhibition in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a difficulty and bottleneck in the clinical treatment of breast cancer due to alack of effective therapeutic targets. Herein, we first report that secernin 2 (SCRN2), an uncharacterized gene in human cancer, acts as a novel tumor suppressor in TNBC to inhibit cancer progression and enhance therapeutic sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition both in vitro and in vivo. SCRN2 is downregulated in TNBC through chaperone-mediated autophagic degradation, and its downregulation is associated with poor patient prognosis. Moreover, SCRN2 impedes the proteasomal degradation of histone-lysine N-methyltransferase 2C (KMT2C) by recruiting Bcl2-associated athanogene 2 to block the interaction of KMT2C with E3 ubiquitin-protein ligase CHIP. Consistently, SCRN2 transcriptionally activates Bcl2-modifying factor by amplifying histone H3 monomethylation at lysine 4 at its enhancer, thereby inducing intrinsic apoptosis. Notably, KMT2C knockdown restores the impaired TNBC progression caused by SCRN2 overexpression both in vitro and in vivo. Furthermore, SCRN2 decreases the expression of key DNA repair-related genes and induces endogenous DNA damage, thus conferring therapeutic sensitivity of TNBC cells to PARP inhibition. Collectively, these findings identify SCRN2 as a novel suppressor of TNBC, reveal its mechanism of action, and highlight its potential role in TNBC therapy.

Identification of putative Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) dual inhibitors for triple-negative breast cancer therapy

Tryptophan catabolism is a central pathway in many cancers, serving to sustain an immunosuppressive microenvironment. The key enzymes involved in this tryptophan metabolism such as indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are reported as promising novel targets in cancer immunotherapy. IDO1 and TDO overexpression in TNBC cells promote resistance to cell death, proliferation, invasion, and metastasis. To date, there are no clinically available small-molecule inhibitors that target these enzymes. Navoximod, a reliable dual-specific inhibitor, resulted in poor bioavailability and modest efficacy in clinical trials restricts its utility. This situation urges the development of a potent drug-like candidate against these key enzymes. A total of 1574 natural compounds were proclaimed and subjected to ADME screening. Subsequently, the resultant compounds were attributed to hierarchical molecular docking and MM-GBSA validation. Ultimately, re-scoring with the aid of combined machine learning algorithms resulted six lead compounds. Captivatingly, NPACT00380 exhibited maximum interaction among the lead compounds. In addition, the scaffold analysis also highlighted that the chromanone moiety of the hit compound boasts anti-cancer activity against breast cancer cell lines. The reliability of the results was corroborated through a rigorous 100 ns molecular dynamics simulation using the parameters including RMSD, PCA and FEL analysis. In light of these findings, it is presumed that the proposed compound exhibits significant inhibitory activity. As a result, we speculate that further optimisation of NPACT00380 could be beneficial for the treatment and management of TNBC.

Metabolomics insights into doxorubicin and 5-fluorouracil combination therapy in triple-negative breast cancer: a xenograft mouse model study.

Breast cancer is one of the most prevalent malignancies and a leading cause of death among women worldwide. Among its subtypes, triple-negative breast cancer (TNBC) poses significant clinical challenges due to its aggressive behavior and limited treatment options. This study aimed to investigate the effects of doxorubicin (DOX) and 5-fluorouracil (5-FU) as monotherapies and in combination using an established MDA-MB-231 xenograft model in female BALB/C nude mice employing advanced metabolomics analysis to identify molecular alterations induced by these treatments. We conducted comprehensive plasma and tumor tissue sample profiling using ultra-high-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry (UHPLC-ESI-QTOF-MS). Each treatment group exhibited unique metabolic profiles in plasma and tumor analysis. Univariate and enrichment analyses identified alterations in metabolic pathways. The combination treatment of DOX + 5-FU induced the most extensive metabolic alterations disrupting key pathways including purine, pyrimidine, beta-alanine, and sphingolipid metabolism. It significantly reduced critical metabolites such as guanine, xanthine, inosine, L-fucose, and sphinganine, demonstrating enhanced cytotoxic effects compared to individual treatments. The DOX treatment uniquely increased ornithine levels, while 5-FU altered sphingolipid metabolism, promoting apoptosis. This in vivo study highlights TNBC's metabolic alterations to chemotherapeutics, identifying potential biomarkers like L-fucose and beta-alanine, and provides insights for improving treatment strategies.

A dual thermo/pH-sensitive hydrogel as 5-Fluorouracil carrier for breast cancer treatment.

Intelligent hydrogels are promising in constructing scaffolds for the controlled delivery of drugs. Here, a dual thermo- and pH-responsive hydrogel called PCG [poly (N-isopropyl acrylamide-co-itaconic acid)/chitosan/glycerophosphate (PNI/CS/GP)] was established as the carrier of 5-fluorouracil (5-FU) for triple-negative breast cancer (TNBC) treatment. The PCG hydrogel was fabricated by blending synthesized [poly (N-isopropyl acrylamide-co-itaconic acid), pNIAAm-co-IA, PNI] with CS in the presence of GP as a crosslinking agent. The interaction between PCG hydrogel compositions was characterized by Fourier transforms infrared, NMR spectroscopy, and scanning electron microscopy. The PCG hydrogel presented an interconnected and porous structure with similar pore size, rapid swelling/deswelling rate in response to both temperature and pH change, and biocompatibility, upon which it was proposed as a great drug carrier. 5-FU had a dual thermo- and pH-responsive controlled release behavior from the PCG hydrogel and displayed an accelerated release rate in an acidic pH environment than in a neutral pH condition. The application of 5-FU-loaded PCG hydrogel exhibited a more promoted anticancer activity than 5-FU against the growth of TNBC cells both in vitro and in vivo. The outcomes suggested that the PCG hydrogel could be an excellent platform for local drug-delivery systems in the clinical therapy of TNBC.

CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer

The energetic demands of proliferating cells during tumorigenesis require close coordination between the cell cycle and metabolism. While CDK4 is known for its role in cell proliferation, its metabolic function in cancer, particularly in triple-negative breast cancer (TNBC), remains unclear. Our study, using genetic and pharmacological approaches, reveals that CDK4 inactivation only modestly impacts TNBC cell proliferation and tumor formation. Notably, CDK4 depletion or long-term CDK4/6 inhibition confers resistance to apoptosis in TNBC cells. Mechanistically, CDK4 enhances mitochondria-endoplasmic reticulum contact (MERCs) formation, promoting mitochondrial fission and ER-mitochondrial calcium signaling, which are crucial for TNBC metabolic flexibility. Phosphoproteomic analysis identified CDK4’s role in regulating PKA activity at MERCs. In this work, we highlight CDK4’s role in mitochondrial apoptosis inhibition and suggest that targeting MERCs-associated metabolic shifts could enhance TNBC therapy.

Insights into the Emerging Therapeutic Targets of Triple-negative Breast Cancer.

Triple-negative Breast Cancer (TNBC), the most aggressive breast cancer subtype, is characterized by the non-appearance of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Clinically, TNBC is marked by its low survival rate, poor therapeutic outcomes, high aggressiveness, and lack of targeted therapies. Over the past few decades, many clinical trials have been ongoing for targeted therapies in TNBC. Although some classes, such as Poly (ADP Ribose) Polymerase (PARP) inhibitors and immunotherapies, have shown positive therapeutic outcomes, however, clinical effects are not much satisfiable. Moreover, the development of drug resistance is the major pattern observed in many targeted monotherapies. The heterogeneity of TNBC might be the cause for limited clinical benefits. Hence,, there is a need for the potential identification of new therapeutic targets to address the above limitations. In this context, some novel targets that can address the above-mentioned concerns are emerging in the era of TNBC therapy, which include Hypoxia Inducible Factor (HIF-1α), Matrix Metalloproteinase 9 (MMP-9), Tumour Necrosis Factor-α (TNF-α), β-Adrenergic Receptor (β-AR), Voltage Gated Sodium Channels (VGSCs), and Cell Cycle Regulators. Currently, we summarize the ongoing clinical trials and discuss the novel therapeutic targets in the management of TNBC.

An engineered-exosome disguised multifunctional nanoplatform for enhanced chemo-photothermal therapy of triple-negative breast cancer

An engineered-exosome disguised multifunctional nanoplatform for enhanced chemo-photothermal therapy of triple-negative breast cancer

Triple-helix β-glucan-based self-assemblies, synthesis, characterization and anticarcinogenic effect.

Triple negative breast cancer (TNBC) seriously endangers women's life and health due to its high invasion and mortality. Reactive oxygen species (ROS) mediated tumor cells apoptosis is considered an effective anticancer approach. Herein, we designed a natural active triple helix β-Glucan (BFP) wrapped single walled carbon nanotubes (SWNTs)-loaded doxorubicin (DOX) self-assembly (BSD) via generating excess ROS to induce oxidative stress damage for TNBC therapy. BSD could directly consume glutathione (GSH) to promote ROS. In vitro results demonstrated that BSD exhibited obvious antitumor effects to breast cancer cells by promoting apoptosis. Un-targeted metabolomics under molecular level identified the specific metabolic targets and unveiled that BSD markedly disturbed multiple metabolic pathways, including purine metabolism, pentose phosphate pathway, glutathione metabolism pathways, amino sugar and nucleotide sugar metabolism and energy metabolism, led to the inhibition of DNA and RNA synthesis, the generation of ROS, the exacerbation of DNA damage, the disruption of cell membrane integrity and the decrease of ATP. In vitro and in vivo oxidative stress assays further verified that BSD significantly promoted intracellular oxidative stress and resulted in cell damage. This study provides theoretical basis for the development and screening of new drugs based on ROS therapy for TNBC.

Food-derived phytochemicals from functional food (Allium sativum) as VEGF-R1 inhibitors: A novel approach for triple-negative breast cancer therapy

Food-derived phytochemicals from functional food (Allium sativum) as VEGF-R1 inhibitors: A novel approach for triple-negative breast cancer therapy

Exploring the potential of Arbacia lixula coelomic fluid peptides as cell cycle and angiogenesis inhibitor for triple-negative breast cancer therapy: In silico study

Exploring the potential of Arbacia lixula coelomic fluid peptides as cell cycle and angiogenesis inhibitor for triple-negative breast cancer therapy: In silico study

Concurrent Amplification of Ferroptosis and Immune System Activation Via Nanomedicine-Mediated Radiosensitization for Triple-Negative Breast Cancer Therapy.

Radiation therapy (RT) is one of the core therapies for current cancer management. However, the emergence of radioresistance has become a major cause of radiotherapy failure and disease progression. Therefore, overcoming radioresistance to achieve highly effective treatment for refractory tumors is significant yet challenging. Here, pH-responsive DSPE-PEoz modified hollow Bi2Se3-RSL3/diABZi (DP-HBN/RA) nanomedicine is designed as a radiation sensitizer for efficient treatment of triple-negative breast cancer by simultaneously amplifying ferroptosis and immune system activation. DP-HBN/RA can efficiently concentrate X-ray radiation energy inside the tumor, thereby promoting precise ionizing radiation exposure in tumor cells to produce large amounts of reactive oxygen species (ROS), leading to lipid peroxidation-induced ferroptosis. Meanwhile, ferroptotic cell death is intensified through the inactivation of GPX4 by RSL3 released from DP-HBN/RA to acidic conditions in the tumor microenvironment. Additionally, DP-HBN/RA enhances RT efficacy to exacerbate unrepairable DNA damage and release DNA fragments that activate the cGAS-STING signal pathway, evoking a systematic immune response. Ingeniously, the released diABZi reinforces cGAS-STING activation to boost the immunology antitumor effect. This work links the induction of ferroptosis and the initiation of systematic immune response to achieve highly effective tumor suppression, which opens up new avenues for future treatments of refractory tumors.

A First Report of Docosahexaenoic Acid‐Clocked Polymer Enveloped Gold Nanoparticles: A Way to Precision Breast Cancer and Triple Negative Breast Cancer Therapy and Its Apoptosis Induction

ABSTRACTFunctionalized gold nanoparticles (GNPs) are extensively utilized in various disciplines due to their excellent bioactivity, biocompatibility, and extended drug half‐life, influenced by the ligands and size that are changed on surfaces. In this study, we successfully fabricated GNPs coated with ligands containing docosahexaenoic acid (DHA) and polyethylene glycol (PEG) clocked by a carboxyl group. These nanoparticles are referred to as MPA@GNPs‐PEG‐DHA. The cytotoxicity results demonstrate that MPA@GNPs‐PEG‐DHA exhibits superior cell selectivity, explicitly inhibiting the proliferation of breast cancerous cells than noncancerous cell lines. Apoptosis is involved in the reduction of cell proliferation by MPA@GNPs‐PEG‐DHA, as demonstrated clearly through many assays measuring apoptotic index, including AO/EB staining, DAPI, annexin V‐FITC staining, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) measurement. The efficacy of MPA@GNPs‐PEG‐DHA in inducing apoptosis was demonstrated by its inhibition of mitochondrial dysfunction by ROS. MPA@GNPs‐PEG‐DHA has the potential to improve the induction of apoptosis in breast cancerous cells.

CBL0137 and NKG2A blockade: a novel immuno-oncology combination therapy for Myc-overexpressing triple-negative breast cancers.

The MYC proto-oncogene is upregulated in >60% of triple-negative breast cancers (TNBCs), it can directly promote tumor cell proliferation, and its overexpression negatively regulates anti-tumor immune responses. For all these reasons, MYC has long been considered as a compelling therapeutic target. However, pharmacological inhibition of MYC function has proven difficult due to a lack of a drug-binding pocket. Here, we demonstrate that the potent abrogation of MYC gene transcription by CBL0137 induces immunogenic cell death and reduces proliferation in MYC-high but not in MYC-low TNBC in vitro. CBL0137 also significantly inhibited the in vivo growth of primary tumors in a human MYC-high TNBC xenograft model (MDA-MB-231). Moreover, CBL0137 inhibited the tumor growth of highly aggressive mouse 4T1.2 syngeneic TNBC model in immunocompetent mice by inhibiting the MYC pathway and inducing Type I interferon responses. Immune profiling of CBL0137-treated mice revealed significantly enhanced tumor-specific immune responses and increased proportions of tumor infiltrating effector CD8+ T cells, CD4+ T cells, and NK cells. CBL0137-induced immune activation also resulted in increased exhaustion of immune effector cells. In particular, NKG2A up-regulation on activated effector cells and of its ligand Qa-1b on tumors in vivo was identified as a possible immune evasive mechanism. Indeed, NKG2A blockade synergized with CBL0137 significantly inhibiting the in vivo growth of 4T1.2 tumors. Collectively, our findings provide the rationale supporting the exploitation of CBL0137-induced anti-tumor immunity in combination with NKG2A blockade to improve the treatment of TNBC expressing high levels of MYC.

Au@109Pd Core-Shell Nanoparticles Conjugated to Panitumumab for the Combined β--Auger Electron Therapy of Triple-Negative Breast Cancer.

Apart from HER2-positive, triple-negative breast cancer (TNBC) is the second most highly invasive type of breast cancer. Although TNBC does not overexpress HER2 receptors, it has been observed that EGFR protein expression is present in this specific type of tumor, making it an attractive target for immune and radiopharmaceutical treatments. In our current study, we used 109Pd (T1/2 = 13.7 h) in the form of a 109Pd/109mAg in vivo generator as a source of β- particles and Auger electrons in targeted radionuclide therapy for TNBC. 109Pd, obtained through neutron irradiation of the 108Pd target, was deposited onto 15 nm gold nanoparticles to form Au@109Pd core-shell nanoparticles, which were then conjugated to the panitumumab antibody. Au@109Pd-PEG-panitumumab nanoparticles were bound, internalized, and partially routed to the nucleus in MDA-MB-231 human breast cancer cells overexpressing EGFR receptors. The Au@109Pd-panitumumab radioconjugate significantly reduced the metabolic activity of MDA-MB-231 cells in a dose-dependent manner. In conclusion, we have found that Au@109Pd-PEG-panitumumab nanoparticles show potential as a therapeutic agent for combined β--Auger electron targeted radionuclide therapy of TNBC. The simultaneous emission of β-, conversion, and Auger electrons from the 109Pd/109mAg generator, similar to 161Tb conjugates, significantly enhances the therapeutic effect. The partial localization of these nanoparticles into the cell nucleus, provided by the panitumumab vector, ensures effective therapy with Auger electrons. This is particularly important for the treatment of drug-resistant TNBC cells.

Body composition as a novel biomarker of recurrence risk in patients with triple-negative breast cancer.

Triple-negative breast cancer (TNBC) patients are at increased risk for recurrence compared to other subtypes of breast cancer. Previous evidence showed that adiposity may contribute to worsened cancer control. Current measures of obesity, such as body-mass index (BMI), are poor surrogates of adiposity, while visceral-to-subcutaneous adiposity ratio (VSR), which can be measured from routine computed tomography (CT) imaging, is a direct adiposity measure. We hypothesized that VSR is a stronger predictor of recurrence compared with BMI in patients with TNBC. This study includes 162 women with stage I-III TNBC who completed standard of care therapy. Measures of body composition, including VSR, visceral adiposity (VA), and subcutaneous adiposity (SA), were estimated using a semi-automated quantitative imaging tool on CT images of the abdomen at the level of L2-L3. Anthropometric measures included BMI and waist circumference and were obtained from CT images. Associations of adiposity measures and recurrence risk were assessed using Fine and Gray competing risk models with death as a competing risk and age at diagnosis and clinical disease stage as covariates. During a median follow-up time of 3.6 years, 55 patients had recurrence. The median BMI at baseline was 30.2 [Quartiles: 26.3-35.2]. Body composition was not associated with overall or locoregional recurrence. VSR was significantly associated with an increased risk of distant recurrence, with a subdistribution hazard ratio of 4.25 (95% CI: 1.06-17.02), p = 0.041. By contrast, BMI was not associated with any recurrence risk. Consistent with our hypothesis, VSR was associated with a significant risk of distant recurrence and therefore may be a prognostic biomarker. Future directions include interventions targeting VSR reduction among patients with TNBC and VSR-directed therapy modulation.

Advancements in clinical research and emerging therapies for triple-negative breast cancer treatment.

Triple-negative breast cancer (TNBC), defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) expression, is acknowledged as the most aggressive form of breast cancer (BC), comprising 15%-20% of all primary cases. Despite the prevalence of TNBC, effective and well-tolerated targeted therapies remain limited, with chemotherapy continuing to be the mainstay of treatment. However, the horizon is brightened by recent advancements in immunotherapy and antibody-drug conjugates (ADCs), which have garnered the U.S. Food and Drug Administration (FDA) approval for various stages of TNBC. Poly (ADP-ribose) polymerase inhibitors (PARPi), particularly for TNBC with BRCA mutations, present a promising avenue, albeit with the challenge of resistance that must be addressed. The success of phosphoinositide-3 kinase (PI3K) pathway inhibitors in hormone receptor (HR)-positive BC suggests potential applicability in TNBC, spurring optimism within the research community. This review endeavors to offer a comprehensive synthesis of both established and cutting-edge targeted therapies for TNBC. We delve into the specifics of PARPi, androgen receptor (AR) inhibitors, Cancer stem cells (CSCs), PI3K/Protein Kinase B (AKT)/mammalian target of rapamycin (mTOR), the transforming growth factor-beta (TGF-β), Ntoch, Wnt/β-catenin, hedgehog (Hh) pathway inhibitors, Epigenetic target-mediated drug delivery, ADCs, immune checkpoint inhibitors (ICIs)and novel immunotherapeutic solutions, contextualizing TNBC within current treatment paradigms. By elucidating the mechanisms of these drugs and their prospective clinical applications, we aim to shed light on the challenges and underscore the beacon of hope that translational research and innovative therapies represent for the oncology field.

HMGB3 Contributes to Anti-PD-1 Resistance by Inhibiting IFN-γ-Driven Ferroptosis in TNBC.

Our previous studies showed HMGB3 expression may correlate with immunotherapy efficacy in breast cancer patients. Here, we investigated whether HMGB3 overexpression has an impact on anti-PD-1 therapy in triple-negative breast cancer (TNBC) and its molecular mechanisms. Animal models were established to observe the effect of HMGB3 on sensitivity to anti-PD-1 treatment. Correlation of HMGB3 expression and ferroptosis preventive proteins in TNBC patients' tissues with anti-PD-1 therapy efficacy was analyzed. The impact of HMGB3 on IFN-γ (Interferon-gamma) inhibitory effects and signaling was examined in human TNBC cells where HMGB3 expression was knocked down using siRNA. Moreover, TNBC cells stably transfected with lentiviral vectors containing cDNA of HMGB3 were also used to confirm the effect of overexpression of HMGB3 on IFN-γ inhibitory effect and signaling. Effect of HMGB3 on IFN-γ-driven ferroptosis and ferroptosis-associated protein expression were also investigated. Correlation of HMGB3 and IRF1 and GPX4 expression in patient's cancer tissue were also investigated. Our results demonstrated that HMGB3 expression contributes to resistance to anti-PD-1 therapy in vivo. HMGB3 expression correlated with treatment efficacy of immunotherapy and survival in TNBC patients. HMGB3 silence decreased resistance of breast cancer cells to IFN-γ cytotoxic effect, while HMGB3 overexpression increased resistance of these cancer cells. HMGB3 silence increased STAT1 phosphorylation and IRF1 expression upon IFN-γ treatment compared with control. Overexpression of HMGB3 inhibited STAT1 phosphorylation and IFN-γ signaling in TNBC cells. Moreover, HMGB3 also increased STAT3 activation and had an effect of interaction between STAT1 and STAT3. HMGB3 overexpression decreased IFN-γ-driven ferroptosis in TNBC cells. HMGB3 increased ferroptosis-inhibitory proteins (SLC7A11, GPX4, and SLC3A2) expression in TNBC cells. Ferroptosis inhibition recovers resistance to anti-PD-1 therapy in vivo. Immunohistochemistry showed HMGB3 expression correlated with ferroptosis-associated proteins and IRF1 expression in breast cancer tissue. HMGB3 contributes to anti-PD-1 resistance by inhibiting IFN-γ-driven ferroptosis in TNBC which suggested HMGB3 is a potential co-target with anti-PD-1 therapy for TNBC.