Non-coding RNAs as modulators of radioresponse in triple-negative breast cancer: a systematic review.

Triple-negative breast cancer (TNBC), characterized by high invasiveness, is associated with poor prognosis and elevated mortality rates. Despite the development of effective therapeutic targets for TNBC, systemic chemotherapy and radiotherapy (RdT) remain prevalent treatment modalities. One notable challenge of RdT is the acquisition of radioresistance, which poses a significant obstacle in achieving optimal treatment response. Compelling evidence implicates non-coding RNAs (ncRNAs), gene expression regulators, in the development of radioresistance. This systematic review focuses on describing the role, association, and/or involvement of ncRNAs in modulating radioresponse in TNBC. In adhrence to the PRISMA guidelines, an extensive and comprehensive search was conducted across four databases using carefully selected entry terms. Following the evaluation of the studies based on predefined inclusion and exclusion criteria, a refined selection of 37 original research articles published up to October 2023 was obtained. In total, 33 different ncRNAs, including lncRNAs, miRNAs, and circRNAs, were identified to be associated with radiation response impacting diverse molecular mechanisms, primarily the regulation of cell death and DNA damage repair. The findings highlighted in this review demonstrate the critical roles and the intricate network of ncRNAs that significantly modulates TNBC's responsiveness to radiation. The understanding of these underlying mechanisms offers potential for the early identification of non-responders and patients prone to radioresistance during RdT, ultimately improving TNBC survival outcomes.

Solid Lipid Nanoparticles, an Alternative for the Treatment of Triple-Negative Breast Cancer.

Within the field of nanomedicine, which is revolutionizing cancer treatment, solid lipid nanoparticles (SLNs) have shown advantages over conventional chemotherapy when tested on cancer cells in preclinical studies. SLNs have proven to be an innovative strategy for the treatment of triple-negative breast cancer cells, providing greater efficiency than existing treatments in various studies. The encapsulation of antineoplastic drugs in SLNs has facilitated a sustained, controlled, and targeted release, which enhances therapeutic efficiency and reduces adverse effects. Moreover, the surface of SLNs can be modified to increase efficiency. For instance, the coating of these particles with polyethylene glycol (PEG) decreases their opsonization, resulting in a longer life in the circulatory system. The creation of positively charged cationic SLNs (cSLNs), achieved by the utilization of surfactants or ionic lipids with positively charged structural groups, increases their affinity for cell membranes and plasma proteins. Hyaluronic acid has been added to SLNs so that the distinct pH of tumor cells would stimulate the release of the drug and/or genetic material. The current review summarizes the recent research on SLNs, focusing on the encapsulation and transport of therapeutic agents with a cytotoxic effect on triple-negative breast cancer.

PCMT1 as a prognostic marker in breast cancer.

INTRODUCTION: Triple-negative breast cancer (TNBC) is one of the most aggressive cancers in women, therefore it is necessary to determine novel prognostic markers to estimate survival and advancement the treatment of the disease. Recently, PCMT1, a protein mediating TNBC immune infiltration, has gained attention as a potential therapeutic target. The aim of the study was to demonstrate the relationship between PCMT1 protein overexpression as a prognostic indicator for patients with TNBC cancer and patient survival. MATERIALS AND METHODS: The study included 64 samples collected from 64 TNBC patients. We used the ImageJ software with the IHC Profiler driver for image analysis. To improve the reliability of the results, we expanded the analysis by including The Cancer Genome Atlas cohort. RESULTS: We observed strong PCMT1 immunoreactivity in breast cancer samples and PCMT1 expression in TNBC was significantly higher than in the control group. Patients with high PCMT1 expression had a significantly lower overall survival rate (60.62% vs. 90.35%, respectively) than patients with low PCMT1 expression. In our study and TCGA groups, PCMT1 expression did not correlate with lymph node involvement and distant metastases but correlated with tumor stage. The results obtained in a larger TCGA group are consistent with those in our research group. Overexpression of PCMT1 was a prognostic marker of shorter survival in patients with TNBC. CONCLUSIONS: The overexpression of the PCMT1 protein in triple negative breast cancer significantly correlated with shorter overall survival. The confirmed association could be a potential prognostic biomarker for patients with TNBC.

Amorphous silica nanoparticles exhibit antitumor activity in triple-negative breast cancer cells.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is mainly treated with cytotoxic chemotherapy. However, this treatment is not always effective, and an important percentage of patients develop recurrence. Nanomaterials are emerging as alternative treatment options for various diseases, including cancer. This work reports the synthesis, characterization, antitumor activity evaluation, and sub-acute toxicity studies of two formulations based on amorphous silica nanoparticles (SiNPs). They are functionalized with 3-aminopropyltriethoxisilane (Si@NH2) and folic acid (FA; Si@FA). The results show that SiNPs reduce the viability and migration of TNBC MDA-MB-231 and 4T1 cell lines and Si@FA do not affect the growth of the mammary nonmalignant HC11 cells. In addition, Si@FA induces reactive oxygen species (ROS) generation and displays antiproliferative and subsequently proapoptotic effects in MDA-MB-231 cells. Moreover, none of the SiNPs cause signs of sub-acute toxicity in mice when administered at 30 mg/kg over a month. In conclusion, these nanosystems display intrinsic antitumor activity without causing toxic in vivo effects, being a promising therapeutic alternative for TNBC.

High Levels of Superoxide Dismutase 2 Are Associated With Worse Prognosis in Patients With Breast Cancer.

OBJECTIVE: Breast cancer is classified based on hormone receptor status and human epidermal growth factor receptor 2 (HER2) expression, including luminal, HER2+, or triple-negative (TNBC). The absence of a therapeutic target in TNBC and the resistance to treatment associated with other subtypes means that research for new biomarkers remains important. In this context, superoxide dismutase 2 (SOD2) has emerged as a potential therapeutic target due to its clinicopathological associations and its ability to predict responses in human tumors. To analyze SOD2 staining in samples obtained from individuals with breast cancer and explore its transcriptional pattern across tumor subtypes. MATERIALS AND METHODS: SOD2 staining was assessed using the immunohistochemistry (IHC) in 80 samples from breast cancer patients. To analyze the expression profile at the transcriptional level, international databases such as cBioPortal (1,980 patients) and PrognoScan were accessed. RESULTS: Significant differences were observed between SOD2 expression analyzed by IHC, and estrogen (p = 0.0008) and progesterone (p = 0.0003) receptors, as well as tumor subtypes (p<0.0001). These differences were found in conjunction with other associations, including clinical and pathological data, such as tumor stage (p = 0.0129), tumor size (p = 0.0296), and node metastasis (p = 0.0486). Moreover, elevated SOD2 expression correlated with an unfavorable prognosis. The in silico analysis revealed a similar pattern, despite operating at the transcriptional level. Moreover, notable correlations were identified between elevated SOD2 expression and worse survival. CONCLUSION: These results highlight the importance of SOD2 in breast cancer, particularly in aggressive subtypes. Increased SOD2 staining correlates with poorer outcomes, suggesting it as a potential therapeutic target.

Association of tumor-infiltrating lymphocytes with clinical outcomes in patients with triple-negative breast cancer receiving neoadjuvant chemotherapy: a systematic review and meta-analysis.

OBJECTIVE: Triple-negative breast cancer (TNBC) presents a clinical challenge as an aggressive tumor, correlated with unfavorable prognosis. Tumor-infiltrating lymphocytes (TILs) have garnered interest as a potential prognostic biomarker. However, the disparity in outcomes between varying TILs rates remains inadequately explored. METHODS: PubMed, Scopus, Web of Science, and Cochrane databases were searched for studies about the prognostic value of TILs in patients with TNBC receiving neoadjuvant chemotherapy. The hazard ratios (HRs) or odds ratios (ORs) were computed for binary endpoints, with 95% confidence intervals (CIs). RESULTS: Twenty-nine studies were included, involving a population of six thousand one hundred sixty-one (80.41%) with TNBC. The cut-off TILs value ranged from 10 to 60%, with 50% being the most related value. Compared with the low-TIL expression group, the disease-free survival (DFS) (HR 0.71; 95% CI 0.61-0.82; p < 0.00001) and overall survival (OS) (HR 0.76; 95% CI 0.63-0.90; p = 0.002) rates showed significant improvement with higher TIL infiltrations. In the subgroup analyses of the lymphocyte subtypes CD4 + and CD8 + , there was statistical significance favoring higher TILs rates in both subtypes, each associated with improved DFS (HR 0.48; 95% CI 0.33-0.71; p = 0.0002) and OS (HR 0.53; 95% CI 0.36-0.78; p = 0.001), regardless of which cell subtype was predominantly infiltrated. The complete pathological response analysis showed better rates for the higher TIL group than the control for both the TIL (OR 1.29; 95% CI 1.13-1.48; p = 0.0003) and Ki-67 (OR 2.74; 95% CI 2.01-3.73; p < 0.00001) analyses. CONCLUSION: Higher expressions of TILs in patients with TNBC were associated with improved significantly DFS, OS, and pCR outcomes.

Proteomic Profiling of HDL in Newly Diagnosed Breast Cancer Based on Tumor Molecular Classification and Clinical Stage of Disease.

The association between high-density lipoprotein (HDL) cholesterol and breast cancer (BC) remains controversial due to the high complexity of the HDL particle and its functionality. The HDL proteome was determined in newly diagnosed BC classified according to the molecular type [luminal A or B (LA or LB), HER2, and triple-negative (TN)] and clinical stage of the disease. Women (n = 141) aged between 18 and 80 years with BC, treatment-naïve, and healthy women [n = 103; control group (CT)], matched by age and body mass index, were included. Data-independent acquisition (DIA) proteomics was performed in isolated HDL (D = 1.063-1.21 g/mL). Results: Paraoxonase1, carnosine dipeptidase1, immunoglobulin mMu heavy chain constant region (IGHM), apoA-4, and transthyretin were reduced, and serum amyloid A2 and tetranectin were higher in BC compared to CT. In TNBC, apoA-1, apoA-2, apoC-2, and apoC-4 were reduced compared to LA, LB, and HER2, and apoA-4 compared to LA and HER2. ComplementC3, lambda immunoglobulin2/3, serpin3, IGHM, complement9, alpha2 lysine rich-glycoprotein1, and complement4B were higher in TNBC in comparison to all other types; complement factor B and vitamin D-binding protein were in contrast to LA and HER2, and plasminogen compared to LA and LB. In grouped stages III + IV, tetranectin and alpha2-macroglobulin were reduced, and haptoglobin-related protein; lecithin cholesterol acyltransferase, serum amyloid A1, and IGHM were increased compared to stages I + II. Conclusions: A differential proteomic profile of HDL in BC based on tumor molecular classification and the clinical stage of the disease may contribute to a better understanding of the association of HDL with BC pathophysiology, treatment, and outcomes.

Antitumoral and Antimetastatic Activity by Mixed Chelate Copper(II) Compounds (Casiopeínas®) on Triple-Negative Breast Cancer, In Vitro and In Vivo Models.

Triple-negative breast cancer (TNBC), accounting for 15-20% of all breast cancers, has one of the poorest prognoses and survival rates. Metastasis, a critical process in cancer progression, causes most cancer-related deaths, underscoring the need for alternative therapeutic approaches. This study explores the anti-migratory, anti-invasive, anti-tumoral, and antimetastatic effects of copper coordination compounds Casiopeína IIIia (CasIIIia) and Casiopeína IIgly (CasIIgly) on MDA-MB-231 and 4T1 breast carcinoma cell lines in vitro and in vivo. These emerging anticancer agents, mixed chelate copper(II) compounds, induce apoptosis by generating reactive oxygen species (ROS) and causing DNA damage. Whole-transcriptome analysis via gene expression arrays indicated that subtoxic concentrations of CasIIIia upregulate genes involved in metal response mechanisms. Casiopeínas® reduced TNBC cell viability dose-dependently and more efficiently than Cisplatin. At subtoxic concentrations (IC20), they inhibited random and chemotactic migration of MDA-MB-231 and 4T1 cells by 50-60%, similar to Cisplatin, as confirmed by transcriptome analysis. In vivo, CasIIIia and Cisplatin significantly reduced tumor growth, volume, and weight in a syngeneic breast cancer model with 4T1 cells. Furthermore, both compounds significantly decreased metastatic foci in treated mice compared to controls. Thus, CasIIIia and CasIIgly are promising chemotherapeutic candidates against TNBC.

Antiapoptotic and Prometastatic Roles of Cytokine FAM3B in Triple-Negative Breast Cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. FAM3B, a secreted protein, has been extensively studied in various types of tumors. However, its function in breast cancer remains poorly understood. METHODS: We analyzed FAM3B expression data from breast cancer patients available at TCGA database and overall survival was analyzed by using the Kaplan-Meier plotter. MDA-MB-231 TNBC tumor cell line and hormone-responsive MCF-7 cell lines were transfected to overexpress FAM3B. We assessed cell death, tumorigenicity, and invasiveness in vitro through MTT analysis, flow cytometry assays, anchorage-independent tumor growth, and wound healing assays, respectively. We performed in vivo evaluation by tumor xenograft in nude mice. RESULTS: In silico analysis revealed that FAM3B expression was lower in all breast tumors. However, TNBC patients with high FAM3B expression had a poor prognosis. FAM3B overexpression protected MDA-MB-231 cells from cell death, with increased expression of Bcl-2 and Bcl-xL, and reduced caspase-3 activity. MDA-MB-231 cells overexpressing FAM3B also exhibited increased tumorigenicity and migration rates in vitro, displaying increased tumor growth and reduced survival rates in xenotransplanted nude mice. This phenotype is accompanied by the upregulation of EMT-related genes Slug, Snail, TGFBR2, vimentin, N-cadherin, MMP-2, MMP-9, and MMP-14. However, these effects were not observed in the MCF-7 cells overexpressing FAM3B. CONCLUSION: FAM3B overexpression contributes to tumor growth, promotion of metastasis, and, consequently, leads to a poor prognosis in the most aggressive forms of breast cancer. Future clinical research is necessary to validate FAM3B as both a diagnostic and a therapeutic strategy for TNBC.

Selective Antineoplastic Potential of Fractionated Caribbean Native Ganoderma Species Extracts on Triple-Negative Breast Cancer Cells.

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 expression. It is known for its high malignancy, invasiveness, and propensity for metastasis, resulting in a poor prognosis due to the absence of beneficial therapeutic targets. Natural products derived from mushrooms have gained significant attention in neoplastic therapy due to their potential medicinal properties. The therapeutic potential of Ganoderma lucidum in breast cancer has been highlighted by our group, suggesting its use as an adjuvant treatment. The present study aims to assess the potential antineoplastic capacity of two Caribbean native Ganoderma species found in Puerto Rico, Ganoderma multiplicatum (G. multiplicatum) and Ganoderma martinicense (G. martinicense). Antiproliferative studies were conducted via cell viability assays after cultivation, harvesting, and fractionation of both species. The obtained results indicate that most of the fractions show some cytotoxicity against all cell lines, but 33% of the fractions (F1, F2, F7, F12) display selectivity towards cancer cell models. We demonstrate for the first time that native Ganoderma species can generate metabolites with anti-TNBC properties. Future avenues will focus on structure elucidation of the most active fractions of these Ganoderma extracts.

Endoplasmic reticulum stress regulates apoptosis and chemotherapeutic via enhancing TNFRSF10B recycling to the cell membrane in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most common malignant tumor in China. The expression and cell surface levels of TNF receptor superfamily member 10B (TNFRSF10B) are associated with apoptosis and chemotherapy. However, the precise molecular mechanisms that govern the regulation of TNFRSF10B remain unclear. MATERIALS AND METHODS: RNA-Seq data related to TNBC chemotherapy resistance were acquired from the GEO database. The mRNA and protein levels of TNFRSF10B were detected using RT-PCR and Western blotting, respectively. Cell Counting Kit-8 (CCK-8) and colony formation assays were used to detect cell proliferation. Annexin V/7-AAD staining was used to evaluate apoptosis. The cell membrane TNFRSF10B was analyzed by Western blotting and immunofluorescence. Inducers and inhibitors of endoplasmic reticulum stress (ERS) were used to assess the effect of ERS on TNFRSF10B localization. RESULTS: TNFRSF10B expression was downregulated in TNBC and was associated with prognosis. TNFRSF10B overexpression inhibits the growth of TNBC both in vivo and in vitro and can partially counteract chemotherapy resistance. ERS activation in TNBC promotes the expression of TNFRSF10B, leading to its enrichment on the cell membrane surface, thereby activating the apoptotic pathways. CONCLUSION: ERS regulates the expression and subcellular localization of TNFRSF10B in TNBC cells. They synergistically affect anti-apoptosis and chemotherapy resistance in TNBC cells.

Clinical and radiological manifestations associated with triple-negative breast cancer in women from northern Peru. A case-control study.

Objective: Triple-negative breast cancer (TNBC) has an aggressive clinical behaviour, with advanced stages at initial diagnostic evaluation, early recurrences and poor survival, so the purpose was to determine the clinical and radiological manifestations associated with TNBC. Materials and methods: A case-control study in women diagnosed with breast cancer from January 2015 to August 2022 at the 'Instituto Regional de Enfermedades Neoplásicas del Norte'. We classified cases (Triple Negative subtype) and controls (Luminal A, Luminal B and HER2) according to immunohistochemistry ical analysis. Bivariate and multivariate logistic regression models were used to calculate the odds ratio (OR) with their respective 95% confidence intervals (CIs). Results: The medical reports of 88 cases and 236 controls were reviewed. Cases were more likely to report pain (p = 0.001), nodules on ultrasound (p = 0.01) and mammography (p = 0.003), superior median size (p < 0.05), posterior enhancement (p = 0.001) and moderate density (p = 0.003). Multivariate analysis identified that TNBC was more likely to have a nodular type lesion by ultrasound (OR: 9.73, 95% CI: 1.10-86.16; p = 0.04), ultrasound lesion larger than 36 mm (OR: 4.99, 95% CI: 1.75-14.17; p = 0.003) and moderate density (OR: 3.83, 95% CI: 1.44-10.14; p = 0.007). Conclusion: There are particular clinical and imaging manifestations of TNBC, showing that radiological lesions that presented characteristics in ultrasound as nodular type lesions larger than 36 mm and in mammography moderate grade density, were associated with this subtype of breast tumours in a Peruvian population.

Triple-Negative Breast Cancer Subclassified by Immunohistochemistry: Correlation with Clinical and Pathological Outcomes in Patients Receiving Neoadjuvant Chemotherapy.

The intrinsic subtype of triple-negative breast cancer (TNBC) is based on genomic evaluation. In this study, we report the survival and pathological complete response (pCR) rates of TNBC patients subtyped by IHC and treated with neoadjuvant chemotherapy (NACT). A retrospective cohort of 187 TNBC patients who received NACT between 2008 and 2017 was used, and IHC subtyping was performed on biopsy specimens before chemotherapy. The subtyping revealed predominantly basal-like tumors (IHC-BL, 61%), followed by basal-like immune-suppressed tumors (IHC-BLIS, 31%), mesenchymal tumors (12.5%), luminal androgen receptor tumors (IHC-LAR, 12%), and basal-like immune-activated tumors (IHC-BLIA, 10.9%). The pCR rate varied among subtypes, with IHC-BLIA showing the highest (30.0%) and IHC-LAR showing the lowest (4.5%). IHC-BLIS led in recurrence sites. Overall and disease-free survival analyses did not show significant differences among subtypes, although IHC-BLIA demonstrated a trend toward better survival, and IHC-mesenchymal, worse. Patients who achieved pCR exhibited significantly better disease-free survival and overall survival than non-responders. This study underscores the potential of IHC-based subtyping in TNBC management, highlighting distinct response patterns to neoadjuvant chemotherapy and potential implications for treatment strategies. Further research is warranted to validate these findings and explore tailored therapeutic approaches for specific TNBC subtypes.

Dynamic changes in B cell subpopulations in response to triple-negative breast cancer development.

Despite presenting a worse prognosis and being associated with highly aggressive tumors, triple-negative breast cancer (TNBC) is characterized by the higher frequency of tumor-infiltrating lymphocytes, which have been implicated in better overall survival and response to therapy. Though recent studies have reported the capacity of B lymphocytes to recognize overly-expressed normal proteins, and tumor-associated antigens, how tumor development potentially modifies B cell response is yet to be elucidated. Our findings reveal distinct effects of 4T1 and E0771 murine tumor development on B cells in secondary lymphoid organs. Notably, we observe a significant expansion of total B cells and plasma cells in the tumor-draining lymph nodes (tDLNs) as early as 7 days after tumor challenge in both murine models, whereas changes in the spleen are less pronounced. Surprisingly, within the tumor microenvironment (TME) of both models, we detect distinct B cell subpopulations, but tumor development does not appear to cause major alterations in their frequency over time. Furthermore, our investigation into B cell regulatory phenotypes highlights that the B10 Breg phenotype remains unaffected in the evaluated tissues. Most importantly, we identified an increase in CD19 + LAG-3 + cells in tDLNs of both murine models. Interestingly, although CD19 + LAG-3 + cells represent a minor subset of total B cells (< 3%) in all evaluated tissues, most of these cells exhibit elevated expression of IgD, suggesting that LAG-3 may serve as an activation marker for B cells. Corroborating with these findings, we detected distinct cell cycle and proliferation genes alongside LAG-3 analyzing scRNA-Seq data from a cohort of TNBC patients. More importantly, our study suggests that the presence of LAG-3 B cells in breast tumors could be associated with a good prognosis, as patients with higher levels of LAG-3 B cell transcripts had a longer progression-free interval (PFI). This novel insight could pave the way for targeted therapies that harness the unique properties of LAG-3 + B cells, potentially offering new avenues for improving patient outcomes in TNBC. Further research is warranted to unravel the mechanistic pathways of these cells and to validate their prognostic value in larger, diverse patient cohorts.

Hexachlorobenzene as a differential modulator of the conventional and metronomic chemotherapy response in triple negative breast cancer cells.

Aim: Triple negative breast cancer (TNBC) is usually treated with high doses of paclitaxel, whose effectiveness may be modulated by the action of environmental contaminants such as hexachlorobenzene. High doses of paclitaxel cause adverse effects such as low cellular selectivity and the generation of resistance to treatment due to an increase in the expression of multidrug resistance proteins (MRPs). These effects can be reduced using a metronomic administration scheme with low doses. This study aimed to investigate whether hexachlorobenzene modulates the response of cells to conventional chemotherapy with paclitaxel or metronomic chemotherapy with paclitaxel plus carbachol, as well as to study the participation of the MRP ATP-binding cassette transporter G2 (ABCG2) in human TNBC MDA-MB231 cells. Methods: Cells were treated with hexachlorobenzene alone or in combination with conventional or metronomic chemotherapies. The effects of treatments on cell viability were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and the nuclear factor kappa B pathway participation was evaluated using a selective inhibitor. ABCG2 expression and its modulation were determined by western blot. Results: Results confirmed that paclitaxel reduces MDA-MB231 cell viability in a concentration-dependent manner. Results also showed that both conventional and metronomic chemotherapies reduced cell viability with similar efficacy. Although hexachlorobenzene did not modify cell viability per se, it did reverse the effect induced by the conventional chemotherapy, without affecting the efficacy of the metronomic chemotherapy. Additionally, a differential modulation of ABCG2 expression was determined, mediated by the nuclear factor kappa B pathway, which was directly related to the modulation of cell sensitivity to another cycle of paclitaxel treatment. Conclusions: The findings indicate that, in human TNBC MDA-MB231 cells, in the presence of hexachlorobenzene, the metronomic combination of paclitaxel plus carbachol is more effective in affecting the tumor biology than the conventional therapeutic administration scheme of paclitaxel.

Implications of tumor-infiltrating lymphocytes in early-stage triple-negative breast cancer: clinical oncologist perspectives.

Breast cancer (BC) is the most common neoplasm in women worldwide and one of the leading causes of female death. The triple-negative subtype, characterized by the absence of hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2), tends to occur in younger patients, be more aggressive and less differentiated. Furthermore, this subtype is considered the most immunogenic and associated with higher levels of tumor cell infiltration, mainly lymphocytes. Tumor-infiltrating lymphocytes (TILs) play a crucial role in the interaction of the host's immune system and cancer cells. The microenvironment is critical in tumor development and progression. Assessment of infiltrating lymphocytes can provide valuable information about the immune response and, given the lack of biomarkers to guide treatment decisions and predict outcomes in triple-negative tumors and can be considered as a potential biomarker. Some evidence suggests that higher levels of these lymphocytes are associated with better responses to systemic treatment, longer progression-free survival and overall survival (OS). However, treatment escalation or de-escalation strategies for triple-negative BC (TNBC) currently do not consider the presence or density of TILs for therapeutic decisions. TILs appear to be useful predictive and prognostic indicators. Further clinical studies are needed to confirm these relationships and integrate TILs as a biomarker consistently into clinical practice. This article summarizes key concepts relating to the role of the immune infiltrate in BC, along with the current status and future prospects regarding TILs as a predictive and prognostic biomarker.

Antineoplastic effect of compounds C14 and P8 on TNBC and radioresistant TNBC cells by stabilizing the K-Ras4BG13D/PDE6δ complex.

Introduction: Breast cancer (BC) is the leading cause of cancer-related deaths among women, with triple-negative breast cancer (TNBC) representing one of the most aggressive and treatment-resistant subtypes. In this study, we aimed to evaluate the antitumor potential of C14 and P8 molecules in both TNBC and radioresistant TNBC cells. These compounds were chosen for their ability to stabilize the complex formed by the overactivated form of K-Ras4BG13D and its membrane transporter (PDE6δ). Methods: The antitumor potential of C14 and P8 was assessed using TNBC cell lines, MDA-MB-231, and the radioresistant derivative MDA-MB-231RR, both carrying the K-Ras4B> G13D mutation. We investigated the compounds' effects on K-Ras signaling pathways, cell viability, and tumor growth in vivo. Results: Western blotting analysis determined the negative impact of C14 and P8 on the activation of mutant K-Ras signaling pathways in MDA-MB-231 and MDA-MB-231RR cells. Proliferation assays demonstrated their efficacy as cytotoxic agents against K-RasG13D mutant cancer cells and in inducing apoptosis. Clonogenic assays proven their ability to inhibit TNBC and radioresistant TNBC cell clonogenicity. In In vivo studies, C14 and P8 inhibited tumor growth and reduced proliferation, angiogenesis, and cell cycle progression markers. Discussion: These findings suggest that C14 and P8 could serve as promising adjuvant treatments for TNBC, particularly for non-responders to standard therapies. By targeting overactivated K-Ras and its membrane transporter, these compounds offer potential therapeutic benefits against TNBC, including its radioresistant form. Further research and clinical trials are warranted to validate their efficacy and safety as novel TNBC treatments.

Low-Density Lipoproteins Increase Proliferation, Invasion, and Chemoresistance via an Exosome Autocrine Mechanism in MDA-MB-231 Chemoresistant Cells.

Dyslipidemias involving high concentrations of low-density lipoproteins (LDLs) increase the risk of developing triple-negative breast cancer (TNBC), wherein cholesterol metabolism and protein translation initiation mechanisms have been linked with chemoresistance. Doxorubicin (Dox) treatment, a member of the anthracycline family, represents a typical therapeutic strategy; however, chemoresistance remains a significant challenge. Exosomes (Exs) secreted by tumoral cells have been implicated in cell communication pathways and chemoresistance mechanisms; the content of exosomes is an outcome of cellular cholesterol metabolism. We previously induced Dox resistance in TNBC cell models, characterizing a variant denominated as variant B cells. Our results suggest that LDL internalization in parental and chemoresistant variant B cells is associated with increased cell proliferation, migration, invasion, and spheroid growth. We identified the role of eIF4F translation initiation factor and the down-regulation of tumor suppressor gene PDCD4, an inhibitor of eIF4A, in chemoresistant variant B cells. In addition, the exomes secreted by variant B cells were characterized by the protein content, electronic microscopy, and cell internalization assays. Critically, exosomes purified from LDL-treated variant B cell promoted cell proliferation, migration, and an increment in lactate concentration. Our results suggest that an autocrine phenomenon induced by exosomes in chemoresistant cells may induce modifications on signaling mechanisms of the p53/Mdm2 axis and activation of p70 ribosomal protein kinase S6. Moreover, the specific down-regulated profile of chaperones Hsp90 and Hsp70 secretion inside the exosomes of the chemoresistant variant could be associated with this phenomenon. Therefore, autocrine activation mediated by exosomes and the effect of LDL internalization may influence changes in exosome chaperone content and modulate proliferative signaling pathways, increasing the aggressiveness of MDA-MB-231 chemoresistant cells.

Assessment of TUFT1 and Rac1-GTP levels in triple-negative breast cancer patients: clinical and pathological correlations.

OBJECTIVE: The primary goal of this study was to investigate the expressions of TUFT1 (Tuftelin) and Rac1-GTP in the cancerous tissues of individuals with triple-negative breast cancer (TNBC). Additionally, we aimed to explore the correlation between TUFT1 and Rac1-GTP expressions and examine the associations of TUFT1 and Rac1-GTP expressions with the clinical and pathological indicators of the patients. METHODS: Ninety-six patients diagnosed with TNBC, scheduled for surgery between May 2022 and November 2022, were enrolled in this study. Cancerous tissue specimens were collected from these patients, and immunohistochemistry was employed to evaluate the levels of TUFT1 and Rac1-GTP expressions in the cancerous tissues. Subsequent to data collection, a comprehensive analysis was conducted to examine the correlation between TUFT1 and Rac1-GTP expressions. Furthermore, we sought to assess the associations of TUFT1 and Rac1-GTP expressions with the clinical and pathological indicators of the patients. RESULTS: The TUFT1 protein was expressed in both the membrane and cytoplasm of TNBC cancer cells, with notably higher expression observed in the cytoplasm. Rac1-GTP was primarily expressed in the cytoplasm. There was a positive correlation between the levels of TUFT1 and Rac1-GTP expressions (χ2 = 9.816, P < 0.05). The levels of TUFT1 and Rac1-GTP protein expressions showed no correlation with patient age (χ2 = 2.590, 2.565, P > 0.05); however, they demonstrated a positive correlation with tumor size (χ2 = 5.592,5.118), histological grading (χ2 = 6.730, 5.443), and lymph node metastasis (χ2 = 8.221, 5.180) (all with a significance level of P < 0.05). CONCLUSION: A significant correlation was identified between the levels of TUFT1 and Rac1-GTP expressions in the cancerous tissues of patients with TNBC, suggesting a close association with the progression of TNBC. The two molecules play significant roles in facilitating an early diagnosis and treatment of TNBC.