Search Results (2,355)

Triple-negative breast cancer (TNBC) and inflammatory breast cancer (IBC) are the most aggressive molecular subtypes of breast cancer. Poor clinical outcomes highlight the pressing need to discover novel targets for the effective treatment of these diseases. LMP7 (β5i/PSMB8), a proteolytic subunit of the immunoproteasome, is implicated in the pathogenesis of multiple myeloma, autoimmune and inflammatory diseases, and inflammation-related cancers. However, the role of LMP7 in TNBC and IBC remains poorly characterized. Here, we evaluated the function of LMP7 in TNBC and IBC using the selective LMP7 inhibitor M3258. In human TNBC patient samples, LMP7 expression correlated strongly with CD8⁺ T cell infiltration and activation markers. M3258 inhibited LMP7 activity, reduced viability, and induced apoptosis in TNBC/IBC cell lines in vitro. In a novel immunocompetent in vivo model of TNBC/IBC, M3258 reduced tumor growth and the tumor abundance of M2 macrophages. Additionally, M3258 activated tumor-infiltrating CD8⁺ T cells and suppressed the expression of specific inflammatory pathway gene signatures in immune cells. Co-culture with M2 macrophages enhanced the invasiveness of TNBC/IBC cells, which was effectively suppressed by M3258 treatment. Our results demonstrate for the first time that LMP7 shapes the pro-tumorigenic microenvironment of TNBC/IBC, in part by modulating the pathogenic role of M2 macrophages. These findings suggest that LMP7 may represent a novel target for therapeutic intervention in TNBC/IBC. Full article

In this article, the synthesis and characterization of chlorin-based photosensitizers for potential applications in photodynamic therapy (PDT) of triple-negative breast cancer (TNBC) are described. The photodynamic efficacy of the synthesized chlorin-desthiobiotin (CDBTN) conjugate and its zinc and indium complexes were compared with the starting unconjugated precursor methyl pheophorbide, and assessed in a TNBC cell line in vitro. The chlorin-desthiobiotin complex aims to target the vitamin receptors upregulated in malignant cancer cells. The synthesized CDBTN was combined with chemotherapeutic agents (paclitaxel, cisplatin or fluorouracil) to evaluate their binary photodynamic efficacy. Cell survival assay in vitro indicated that the chlorin-vitamin conjugate CDBTN—alone and in combination with paclitaxel or fluorouracil—is photoactive against the TNBC cell line, but not when combined with cisplatin. The combination index (CI) calculated using the Chou-Talalay method indicated synergism of CDBTN and fluorouracil combination, aligning with the in vitro assay. The photodynamic cytotoxicity of CDBTN was also evaluated in vivo using the hydra as a novel model organism. This study is the first to show the use of the aquatic hydra organism in assessing photodynamic activity of the photosensitizer alone or in combination with chemotherapeutic agents. In vivo results with hydras indicated that the CDBTN-cisplatin combination is more phototoxic than CDBTN-paclitaxel or CDBTN-fluorouracil binary treatment. With the proper adjustment of concentration and light dosage, the synthesized photosensitizer can provide promising application in binary chemotherapy PDT treatment of TNBC. Full article

Introduction: A potential prognostic biomarker for predicting the response to immunotherapy in breast cancer (BC) is tumor-infiltrating lymphocytes (TILs). The purpose of this research is to examine if preoperative characteristics of breast magnetic resonance imaging (MRI) may be used to predict TIL levels in a group of BC patients. In addition, we aimed to assess any potential relationship between the various tumor biology subgroups and MR imaging characteristics. Materials and Methods: This retrospective analysis comprised 145 participants with histologically confirmed BC who had preoperative DCE MRI. We collected and examined patient information as well as tumor MRI features, such as size and shape, edema, necrosis, multifocality/multicentricity, background parenchymal enhancement (BPE), and apparent diffusion coefficient (ADC) values. We divided patients into two groups based on their TIL levels: low-TIL (<10%) and high-TIL groups (≥10%). Following core needle biopsy, tumors were categorized as Luminal A, Luminal B, HER2+, and Triple Negative using immunohistochemical analysis. TIL levels were correlated with tumor biological profiles and MRI features using both parametric and non-parametric tests. Results: Patients were categorized as having a high TIL level (≥10%; 54/145 patients) and a low TIL level (<10%; 91/145 patients) based on the median TIL level of 10%. Of the lesions, 13 were HER2-positive, 16 were Triple Negative, 49 were Luminal A, and 67 were Luminal B. Higher TIL levels were statistically correlated with TNBC (11/16 individuals, p: 0.007). ADC values (p = 0.01), BPE levels (p = 0.008), and TIL levels were all significantly negatively correlated. Significantly more homogenous enhancement was seen in tumors with elevated TIL levels (p = 0.001). The ADC values and the enhancing characteristics were the most important factors in predicting TIL levels, according to logistic regression analysis, and when combined, they demonstrated the strongest ability to distinguish between the two groups (AUC = 0.744). Conclusions: MRI features, particularly ADC values and enhancement characteristics, may play a pivotal role in the assessment of TIL levels in BC before surgery. This could help patients to better customize treatments to the features of their tumors. 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

Background/Objectives: Triple-negative breast cancer (TNBC) is a highly aggressive subtype with limited therapeutic options, and identifying reliable biomarkers for diagnosis and prognosis is crucial for improving patient outcomes. Mitochondrial DNA (mtDNA) copy number has been linked to an increased risk of developing various types of cancer, including breast cancer. However, there is a lack of understanding regarding how mtDNA copy number variations may influence the development and progression of TNBC. Methods: This study investigated mtDNA copy number in TNBC tumors and corresponding normal breast tissues from 23 TNBC patients who received neoadjuvant chemotherapy. The relative mtDNA copy number was estimated using quantitative PCR for the NADH dehydrogenase subunit 1 (ND1) and subunit 5 (ND5) regions. Results: The results showed a significant decrease in mtDNA copy number in TNBC tumor tissues compared to corresponding normal breast tissue. However, no significant correlation was found between mtDNA content and clinical parameters such as age, tumor size, or chemotherapy response. Conclusions: These results suggest that while mtDNA content decreases in TNBC tumors, it may not directly influence these clinical characteristics. Despite some inconsistencies in the literature regarding mtDNA dynamics in cancer, this study supports the potential of mtDNA as a biomarker for TNBC. Larger cohort studies are needed to further validate these results and explore the role of mtDNA in guiding personalized treatment strategies for TNBC patients. 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

Luminal B breast cancer (LBBC) represents an aggressive, high-grade ER+ disease, associated with a high proliferation rate, higher mutation burden, and higher probability of eliciting the immune response. Clinical and pathological data from 89 patients of stage II-III, triple-negative (TN), and luminal B-like BC (LB-like BC) were included in the analysis. All patients were submitted to neoadjuvant chemotherapy (NACT). Quantitative and qualitative evaluations of TILs (Tumor-Infiltrating Lymphocytes) were performed on tissue microarrays constructed from pretreatment core-needle biopsy tumor specimens. The proportion of stromal TILs, CD8, CD4, and PD-L1 positive (+) immune cells (IC), as well as the number of FOXP3, CTLA4, and HSP-70+ IC, was observed concerning tumor immunophenotype, traditional clinicopathological prognostic factors, and tumor response to NACT. There was no statistically significant difference in the proportion of stromal TILs between the LB-like and TNBC (p = 0.344) cohorts. However, a higher CD4/CD8 ratio was associated with the TNBC biology (p = 0.018) and within the LB-like BC cohort with a high proliferation index and metastatic nodal involvement (p = 0.045, p = 0.015). Within the LB-like BC cohort, a higher expression of PD-L1 and HSP70+ IC was associated with a high proliferation index of tumor cells (p = 0.018, p = 0.040), massive metastatic nodal involvement (p = 0.002, p = 0.026), and higher stages of disease (p = 0.004, p = 0.042). Better response to NACT was associated with higher numbers of HSP70+ IC and higher proportions of CD8+ cells within the LB-like BC cohort (p = 0.045, p = 0.012). Routine evaluation of immune markers and HSP70 may help identify high-risk patients of LB-like breast cancer who would have a better response to NACT. Full article

Introduction: This study investigates the distribution and interaction of three polymorphisms—XRCC1 (rs1799782), CHEK2 (rs17879961), and XPD (rs238406)—in Romanian breast cancer patients, aiming to understand their association with histopathological subtypes, age, and BMI. Materials and Methods: This retrospective study analyzed 36 breast cancer patients from a Romanian clinic (2020–2024) with complete genetic data for XRCC1 (rs1799782), CHEK2 (rs17879961), and XPD (rs238406). The patients had invasive, non-metastatic breast cancer and no history of other cancers. Statistical analysis with Jamovi included descriptive stats, McNemar’s test for genotype associations, and multinomial logistic regression to explore links between variants, age, BMI, and tumor subtypes. Results: McNemar tests showed no significant association between XRCC1 and CHEK2 (p = 0.180), nor between XRCC1 and XPD (p = 0.03) or XPD and CHEK2 (p = 0.049) after applying the Bonferroni correction (α = 0.0167), indicating no statistically significant genetic dependency among these variants. A multinomial logistic regression model found that genetic variants, BMI, and age significantly predicted breast cancer subtypes, particularly CDI TNB. All predictors remained significant in the comparisons of CDI TNB vs. CDI LB/CDI LA. Notably, these associations remained unchanged even after applying the Bonferroni correction (α = 0.0021), confirming the robustness of the findings. Conclusions: This study identifies significant associations between XRCC1, CHEK2, and XPD gene variants and CDI TNB, suggesting a role of DNA repair deficiencies in its pathogenesis. Protective genotypes were under-represented in TNB cases. Limited links with luminal subtypes highlight TNB’s distinct genetic profile. Results support further research on these polymorphisms as markers for TNB risk and precision treatment. Full article

Background/Objectives: ADCs bring an innovative strategy to cancer treatment by conjugating powerful cytotoxic agents to the specificity of monoclonal antibodies. This review discusses recent advancements and challenges in the field of ADCs, along with future potential applications. Methods: Studies focused on the development of ADCs were reviewed. These include the effects of payload improvements, linker technologies, antibody engineering, and ADC internalization, which were particular topics of examination regarding their role in pancreatic ductal adenocarcinoma (PDAC) and triple-negative breast cancer (TNBC). The efficacy of some ADCs for pancreatic and breast cancers was compared. Results: In TNBC, ADCs such as sacituzumab govitecan and trastuzumab deruxtecan have improved progression-free survival in advanced cases. In contrast, PDAC ADC development is challenged by low antigen density and poor internalization; despite evidence of target engagement in early trials targeting mesothelin and MUC1, ADCs for PDAC have yet to achieve significant clinical efficacy or regulatory approval. Conclusions: While ADCs have significantly advanced treatment options in TNBC, PDAC remains a difficult target due to its stroma-rich microenvironment and lack of high-density, tumor-specific antigens. This article emphasizes the need for tailor-made ADC designs to enhance results in various types of cancers and provides valuable insight into future advancements in precision oncology. Full article

Arabinoxylans (AX) are functional biopolymers, the main non-starch polysaccharides in cereals and other plants. AX is composed of xylose and arabinose, and the ester-linkage of ferulic acid to arabinose confers its bioactive properties. The backbone of AX resembles that of glycosaminoglycans, a major component of the human extracellular matrix. This study explores the potential of wheat bran AX-based scaffolds as a novel platform for the growth and development of triple-negative breast cancer (TNBC) cells, an aggressive form of breast cancer. Importantly, patients face the worst prognosis due to the stemness of the TNBC cells and the formation of hypoxic cell clumps. Wheat bran constitutes 15–25% of the byproducts after milling and adds limited economic value. We have extracted AX from wheat bran (WBAX) and developed soft scaffolds with Na-alginate. The scaffolds were seeded with the triple-negative breast cancer cell line MDA-MB-231. Over 21 days, cell growth and development, cell migration within the hydrogels, and the formation of hypoxic regions within cell clumps were observed. These findings suggest that WBAX-based scaffolds provide a conducive environment for TNBC cell proliferation and development, offering a promising avenue for further research into cancer cell biology and potential therapeutic applications. Full article

Background: The predictive value of muscle-related indicators in triple-negative breast cancer (TNBC) patients undergoing neoadjuvant chemotherapy (NAC) remains unclear. This study aimed to evaluate the association between the skeletal muscle density (SMD) and clinical variables related to the physical reserve with respect to its impact on the pathologic complete response (pCR). Methods: We retrospectively analyzed TNBC patients who underwent NAC at Seoul St. Mary’s Hospital, Catholic University of Korea, from March 2021 to March 2024, via receiving paclitaxel/carboplatin followed by doxorubicin/cyclophosphamide, with or without pembrolizumab. Muscle indices were assessed from CT measurements of the entire cross-sectional muscle area at the L3 level using commercial deep learning software (ClariMetabo version 1.03). Results: A total of 144 patients were included, where 102 received chemoimmunotherapy (NACIT) and 42 received chemotherapy alone (NACT). A higher SMD was significantly associated with a younger age, lower BMI, and fewer comorbidities. In the NACIT group, patients in the high-SMD group (n = 68) demonstrated a higher relative dose intensity (p = 0.003) and improved pCR rates (63.2% vs. 44.1%, p = 0.066) compared with the low-SMD group (n = 34). The multivariable regression analysis identified a higher SMD (per 5-unit increment: OR = 1.67, p = 0.003) and increased PD-L1 combined positive score (per 10-unit increment: OR = 1.38, p = 0.019) as independent predictors of a pCR. The event-free survival was significantly longer in the high-SMD group (p = 0.017) and among patients that achieved a pCR (p < 0.001). In the NACT group, the SMD was not associated with a pCR or survival. Conclusions: The CT-measured SMD reflected the physical reserve in the TNBC patients that received NAC. Alongside the CPS, SMD may serve as a predictive marker for NACIT efficacy. 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

Breast cancer (BC) is globally becoming a great challenge, being both the most diagnosed cancer and the leading cause of death in women. In addition to cancer cells, many bacteria co-inhabit BC, which differ in type and number from the resident microbiota found in healthy breast tissue. While many reports have demonstrated the ability of different bacteria to dysregulate BC’s metabolites, the reciprocal effect of these metabolites on the bacterial microbiota has not yet been investigated. Herein, we assess the effect of conditioned media (CM) from a triple-negative BC cell line (MDA-MB-231) on the metabolic profile of Pseudomonas aeruginosa (P. aeruginosa), an important breast resident Gram-negative bacteria that influence oncogenesis. Optical density and scanning electron microscopes were used to assess the impact of MDA-MB-231-CM (BC-CM) on P. aeruginosa growth and morphological changes, respectively. In addition, liquid chromatography–high-resolution mass spectrometry was used to identify metabolic changes in P. aeruginosa and their secretomes in response to the BC-CM. The BC-CM significantly suppressed the growth of P. aeruginosa in the log phase and induced concentration-dependent cytopathological changes in their cell walls. The metabolites of P. aeruginosa were dysregulated considerably depending on the time of exposure to the BC-CM. When treated with the BC-CM, P. aeruginosa induced the purine alkaloid spliceostatin (FR901464), a prominent antitumor metabolite. The BC-CM also promoted other P. aeruginosa metabolites such as amino acids, phosphoribosyl-AMP, 2-aminoacetophenone, pyochelin I, guanosine monophosphate, riboflavin, and terpenoids, which are capable of interfering with oncogenesis. Nine of the significantly identified metabolites from the 0–3 h comparison and four of those identified from the 0–6 h comparison have potential roles in influencing cancer cell behavior. Our findings demonstrate the ability of triple-negative BC-CM not only to alter the growth and morphology of P. aeruginosa but also to modulate their metabolic profile. A better understanding of the influence of BC on certain resident breast microbiomes, such as P. aeruginosa, may open a new therapeutic intervention opportunity for the treatment of cancer. Full article

A characteristic of triple-negative breast cancer (TNBC) is the epigenetic regulation of tumor suppressor genes, leading to TNBC heterogeneity and treatment resistance in patients. TNBC exhibits high methylation rates, leading to the silencing of numerous tumor suppressor genes. DNA methyltransferase inhibitors (DNMTis) have shown limited clinical efficacy in TNBC treatment. This study aims to uncover a target that could be used to reverse the epigenetic silencing of tumor suppressor genes in TNBC. The Western blot analysis demonstrated that ROR1 knockdown, an oncofetal gene, reduced DNMT3A and DNMT3B protein expression in the TNBC cell lines MDA-MB-231 and HCC1806, as well as a non-malignant breast cell line, MCF10A. The reduced representation bisulfite sequencing (RRBS) analysis identified differential methylation of CREB3L1 when ROR1 is knocked down in TNBC cell lines. CREB3L1 is a transcription factor that plays tumor-suppressive roles in TNBC and is commonly epigenetically silenced in patients. This study shows that ROR1 requires pSTAT3 activation to upregulate DNMT3A and DNMT3B expression to induce CREB3L1 epigenetic silencing in TNBC. ROR1 knockdown resulted in the re-expression of CREB3L1 in TNBC cells. The data provide evidence that ROR1 inhibition, in combination with DNMTis, could enhance patient outcomes as a therapeutic approach for TNBC. Full article

Background: Breast cancer stem cells (CSCs), particularly those enriched in triple-negative breast cancer (TNBC), are key contributors to tumor recurrence, metastasis, and resistance to therapy. CSCs often undergo epithelial-to-mesenchymal transformation (EMT), enhancing their invasiveness. Immune-based strategies that selectively target CSC/EMT antigens offer a promising therapeutic approach. Methods: Twelve candidate CSC/EMT-associated proteins were identified through a systematic literature review. Human serum samples were assessed for antigen-specific IgG using ELISA. Th1/Th2 cytokine profiles, in response to predicted MHC II epitopes, were measured by ELISPOT in PBMCs. Epitope immunogenicity and tumor inhibition were evaluated in murine models, using either TNBC or luminal B syngeneic breast cancer cell lines. Results: Six of the candidate proteins (SOX2, YB1, FOXQ1, MDM2, CDH3, CD105) elicited antigen-specific IgG in human serum. Th1-selective epitopes, defined by high Th1/Th2 ratios, were identified for five of these proteins. Immunization of mice with peptide pools derived from CD105, CDH3, MDM2, SOX2, and YB1 induced significant antigen-specific IFN-γ responses. Tumor growth was significantly inhibited in the vaccinated mice across both the TNBC and luminal B breast cancer models, with mean tumor volume reductions ranging from 61% to 70%. Conclusions: CSC/EMT-associated antigens are immunogenic in humans and can be targeted using Th1-selective epitope-based vaccines. Immunization with these epitopes effectively inhibits tumor growth in multiple murine models of breast cancer. These findings support further clinical evaluation of CSC/EMT-targeted vaccines, especially for high-risk or advanced-stage breast cancer patients. Full article