Search Results (2,068)

Triple negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer characterized by the absence of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), resulting in limited options for targeted therapy and high rates of metastasis, recurrence and death. Extracellular vesicles (EVs) have emerged as central mediators of TNBC pathophysiology, functioning as key intercellular communication vehicles transporting oncogenic proteins, nucleic acids; lipids, and metabolites. These EV-mediated interactions promote tumor microenvironment (TME) remodeling, immune evasion, metastatic niche formation, and therapeutic resistance. Given their stability, accessibility, and molecular complexity, EVs also represent promising diagnostic and prognostic biomarkers for TNBC. Advances in isolation and molecular profiling technologies have enabled the identification of EV-associated signatures that predict therapeutic response and stratify patient risk. Beyond their utility as biomarkers, EVs are rapidly emerging as therapeutic targets and delivery platforms, demonstrating efficacy in transporting chemotherapeutics, RNA-based therapeutics, immune modulators, and photosensitizers with enhanced targeting specificity and therapeutic efficiency. Collectively, EVs play a multifaceted role in TNBC biology, serving simultaneously as drivers of disease progression, minimally invasive biomarkers, and versatile therapeutic vehicles. The integration of EV-centered diagnostics, multi-omic profiling, and engineered therapeutics holds significant potential to transform TNBC management and advance precision oncology for this challenging breast cancer subtype. Full article

Background/Objectives: While traditional transcriptomics and single-cell RNA sequencing can reveal differences in cell type and gene expression, they cannot provide spatial information within tissues. Spatial transcriptomics (ST), as an emerging technology in recent years, has achieved significant progress in resolving gene expression along the spatial dimension. This technology quantifies gene expression at defined spatial coordinates and describes the spatial distribution of transcripts and the co-localization patterns between cells within intact tissue, allowing for an integrated analysis of molecular and spatial information. This review aims to systematically trace the development of ST and highlight its application value in breast cancer research. Methods: We systematically reviewed the recent literature on ST platforms, on combined analyses of single-cell RNA sequencing (scRNA-seq) and ST, and on integrated spatial multi-omics in breast cancer. Key topics include tumor microenvironment organization, intra-tumor heterogeneity, the spatial distribution of immune cells, cancer-associated fibroblast function, treatment-response prediction, and personalized-treatment strategy development. Results: ST can characterize the spatial organization of interactions between breast cancer cells and the tumor microenvironment, describe the spatial dimensions of tumor heterogeneity, and provide multi-dimensional information that may support refined subtype classification and prognostic assessment. Existing studies indicate that ST shows significant potential to inform personalized treatment strategies, but the technology also faces bottlenecks in data integration, spatial resolution, standardization, and the need for functional validation. Conclusions: ST provides an important tool for an in-depth description of the complex spatial organization within breast cancer tumors. When integrated with functional perturbation, longitudinal cohorts, and orthogonal omics, it has the potential to ultimately improve clinical outcomes for breast cancer patients. Full article

Chromosomal instability (CIN) arising from mitotic errors is a hallmark of cancer progression, yet how specific spindle assembly factors are co-opted to support aggressive tumor phenotypes remains incompletely understood. Hepatoma Upregulated Protein (HURP/DLGAP5), a Ran-regulated microtubule-associated protein essential for kinetochore fiber stabilization and chromosome congression, is frequently overexpressed in aggressive cancers. Here, we investigated HURP’s role across a breast cancer metastatic gradient—immortalized MCF10A, the low-metastatic luminal T47D, and the highly metastatic triple-negative MDA-MB-231 cell lines—integrating quantitative spindle analysis, kinetochore tension measurements, spindle checkpoint profiling, migration dynamics, and three-dimensional spheroid modeling. We show that total HURP protein levels increase with metastatic potential, yet spindle-bound HURP is paradoxically reduced in MDA-MB-231 cells, indicating cytoplasmic mislocalization despite increased total protein levels. HURP silencing induced cell-line-specific defects: moderate disorganization and misorientation in MCF10A and T47D cells, but catastrophic spindle collapse, apoptosis, and G2/M arrest in MDA-MB-231 cells. Mechanistically, HURP depletion disrupted the spindle-associated levels and distributions of TPX2, Aurora-A, and NuMA in a subtype-dependent manner, implicating HURP as a context-dependent stabilizer of this mitotic regulatory axis. HURP loss reduced interkinetochore tension in all cell lines, but only MCF10A and T47D cells mounted a proportional BubR1-dependent checkpoint response; MDA-MB-231 cells showed reduced checkpoint signaling, consistent with constitutive spindle assembly checkpoint (SAC) attenuation in triple-negative breast cancer. Beyond mitosis, HURP depletion impaired collective migration and converted MDA-MB-231 cells from super-diffusive, amoeboid-like motility to sub-diffusive behavior, while minimally affecting the less aggressive cell lines. HURP-depleted MDA-MB-231 spheroids were significantly larger, less compact, and less spherical than controls, linking spindle regulation to tissue-level architectural coherence. These findings establish HURP as a multifunctional regulator coordinating mitotic fidelity, migration plasticity, and tumor architecture in breast cancer, with a selective dependency in highly metastatic cells, positioning it as a promising therapeutic target for aggressive breast cancers. Full article

Background: Breast cancer (BC) is a biologically heterogeneous disease, with molecular subtypes differing fundamentally in terms of aggressiveness, metabolic behavior, and therapeutic response. Conventional ¹⁸F-FDG PET provides semi-quantitative assessment of glucose-analogue uptake using the standardized uptake value (SUV), whereas dynamic PET with Patlak analysis can estimate kinetic parameters such as the net influx rate constant (K_i) and the volume of distribution (V_d). However, the interpretation of these parameters in breast tissue remains insufficiently defined, and data across BC subtypes are limited. This proof-of-concept study explored the feasibility of deriving preliminary reference ranges for non-pathological breast tissue and describing subtype-specific patterns of kinetic parameters. Methods: Six breast cancer patients affected by Luminal (n = 4) or triple negative BC (TNBC, n = 3) and six control patients underwent dynamic ¹⁸F-FDG PET/CT. Patlak kinetic analysis generated parametric K_i and V_d maps. Lesion-level first-order radiomics features were extracted for each breast lesion. Non-lesional breast volumes (contralateral breast and breast excluding disease) were characterized to derive exploratory physiological reference ranges. Results: In control whole-breast tissue, median values were SUV 0.28 g/mL, K_i 0.056 mL/min/100 mL, and V_d ~9%. Non-lesional breast tissue in BC remained statistically concordant with controls. Lesion analysis suggested a possible metabolic gradient across subtypes: Luminal B with low proliferation activity exhibited lowest K_i (0.34 mL/min/100 mL), and highest V_d (~39%); Luminal A showed intermediate K_i (1.93 mL/min/100 mL) and V_d (~27%) values; TNBC showed higher K_i (3.02 mL/min/100 mL) with a greater proportion of zero-valued V_d voxels. Conclusions: This exploratory study suggests that parametric maps may be feasible for describing physiological breast tissue kinetic ranges and for exploring subtype-associated metabolic differences in BC. The observed K_i and V_d patterns may reflect differences in glucose phosphorylation and tracer distribution across tumor phenotypes, but the biological meaning of Patlak-derived parameters requires further methodological and histopathological validation. Larger prospective studies are needed before these parameters can be considered clinically applicable imaging biomarkers. Full article

Background: Invasive lobular carcinoma (ILC) of the breast has a unique metastatic pattern due to E-cadherin deficiency, with a predilection for peritoneal, gastrointestinal, and pelvic organ involvement. Ovarian metastasis from ILC is rare but can mimic primary ovarian cancer clinically and radiologically, leading to misdiagnosis and unnecessary radical surgery. This study aimed to summarize the imaging features of ovarian metastasis from ILC and analyze the causes of misdiagnosis, while highlighting the value of preoperative biopsy. Methods: Clinical and imaging data of six patients with pathologically confirmed ovarian metastasis from ILC were retrospectively analyzed. All six patients were female (age range 33–65 years), had a history of breast cancer (ILC subtype), and were found to have ovarian masses either during follow-up or at initial diagnosis. Imaging findings of the ovaries, peritoneum, and ascites were analyzed and compared with initial clinical diagnoses and pathological results. Results: Among the six patients, five were initially clinically misdiagnosed as having primary ovarian cancer and underwent unnecessary total hysterectomy with bilateral salpingo-oophorectomy. One patient (case 6) was correctly diagnosed via percutaneous biopsy of the omentum and skin nodules, which confirmed metastatic ILC, thereby avoiding unnecessary gynecological surgery. Imaging findings: All six patients had bilateral ovarian masses, appearing as solid or cystic-solid lesions. Peritoneal changes were observed in four cases. Ascites was present in five cases. Laboratory findings showed marked variability in CA125 levels (normal in three cases, elevated in three cases). Immunohistochemistry confirmed breast origin in all cases (GATA3+, PAX8−, E-cadherin−). In case 6, after four cycles of chemotherapy (albumin-bound paclitaxel + carboplatin + bevacizumab), follow-up CT demonstrated significant reduction in ovarian masses and regression of peritoneal and omental lesions. Conclusions: Ovarian metastasis from ILC is easily misdiagnosed as primary ovarian cancer without histologic confirmation, leading to unnecessary radical surgery. However, as demonstrated in case 6, percutaneous biopsy of accessible metastatic sites (omentum, peritoneum, or skin nodules) can establish the correct diagnosis and guide systemic therapy, thereby avoiding unnecessary surgery. In case 6, the ILC ovarian metastasis showed a favorable response to chemotherapy, but this single-case finding requires cautious interpretation as ILC is generally considered less chemosensitive than invasive ductal carcinoma. In patients with a history of breast cancer or with suspected metastatic disease, ILC metastasis should be included in the differential diagnosis of ovarian masses. Full article

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by limited actionable targets, early recurrence, metastatic propensity, and variable responses to immune checkpoint blockade. Therapeutic resistance is closely associated with myeloid immunosuppression, in which tumor-associated macrophages (TAMs) promote T-cell exclusion, stromal remodeling, angiogenesis, metabolic dysfunction, and resistance to cytotoxic and immune-based therapies. Anthraquinone compounds, including emodin, aloe-emodin, rhein, and chrysophanol, may support TAM reprogramming by regulating tumor-cell stress responses, endoplasmic reticulum stress, immunogenic cell death-associated signaling, redox balance, immunometabolism, and STAT3/NF-κB-related inflammatory pathways. However, poor aqueous solubility, heterogeneous biodistribution, unstable systemic exposure, and potential off-target toxicity limit their translational development. Liposomal delivery offers a formulation strategy to improve solubilization, biodistribution, TAM-associated uptake/engagement, intracellular release, and therapeutic exposure windows. This review discusses anthraquinone-loaded liposomes for TAM reprogramming in TNBC by integrating mechanistic rationale, evidence boundaries, delivery logic, formulation determinants, and translational challenges, with particular attention to stress chaperone proteins, lipid composition, vesicle lamellarity, membrane phase state, responsive release, clinically relevant liposomal formulations, and clinical developability. Overall, anthraquinone-loaded liposomes are better positioned as immune microenvironment recalibration platforms or synergistic modulators in combination therapy rather than as standalone cytotoxic agents for TNBC. Full article

Background/Objectives: Tumor-infiltrating lymphocytes (TILs) are recognized predictors of response to neoadjuvant chemotherapy (NACT) and prognosis in breast cancer, particularly in triple-negative (TN) and HER2-positive subtypes. However, the additional predictive value of morphological features of the inflammatory infiltrate beyond TIL quantification is not fully established. We aimed to assess the predictive value of TILs for response to NACT in breast cancer and to determine whether morphological characteristics of the inflammatory infiltrate enhance predictive accuracy. Methods: We analyzed 477 patients with stage II–III breast cancer treated with NACT between 2009 and 2016. Diagnostic core needle biopsies were prospectively re-evaluated. TILs were quantified according to International TILs Working Group recommendations. Morphological features of the infiltrate, including cell composition (lymphocytic vs. plasma cell-rich), heterogeneity, and localization, were evaluated using standardized criteria. Pathologic complete response (pCR) was defined as absence of invasive tumor in the breast and in the axillary lymph nodes (ypT0/Tis ypN0). Univariate and multivariate logistic regression analyses were performed to assess the predictive value of TILs (quantitative and morphological assessment) to achieve pCR for the entire cohort and by surrogate molecular subtype. Results: A TIL cutoff of >20% was identified as optimal for predicting pCR. High TILs were significantly associated with high-grade tumors, elevatedKi67, HER2-positive and TN subtypes, presence of plasma cells, and intraepithelial and heterogeneous infiltrates. In the overall cohort, TILs > 20% significantly increased the likelihood of pCR (OR 3.9, 95%IC 2.5–6.0, p < 0.001) and was an independent predictor of pCR. A combined variable incorporating TIL level and homogeneity improved predictive performance, with homogeneously high TILs emerging as a strong predictor of pCR (OR 5.521, 95%CI 3.174–9.603, p < 0.01). Plasma cell-rich and intraepithelial infiltrates were also associated with higher pCR rates (respectively, OR 2.7, 95%CI 1.5–5.0, p = 0.001 and OR 2.8, 95%CI 1.6–5.0, p < 0.001). Subtype-specific analyses confirmed the predictive value of TILs in TN tumors, but not in HER2-positive ones. Notably, in luminal B-like tumors, high TILs were the only independent predictor of response (OR 17.982, 95%CI 3.115–103.815, p = 0.001). Conclusions: TIL assessment on routine H&E-stained biopsies is a robust predictor of response to NACT in breast cancer that is readily available, cost-neutral and does not require additional techniques. Integration of simple morphological features significantly enhances predictive accuracy and may refine treatment stratification, particularly in luminal B-like tumors. Full article

Background/Objectives: Melatonin is a multifunctional indoleamine with recognized antitumor activity; however, its subtype-specific effects in breast cancer remain incompletely understood. This study aimed to investigate the impact of melatonin on cellular and metabolic processes associated with tumor progression in two human breast cancer cell lines representing distinct molecular subtypes: MCF-7 (luminal A) and MDA-MB-468 (triple-negative). Methods: Breast cancer cells were treated with micromolar concentrations of melatonin, and assays were performed to evaluate cell viability, migration, invasion, mitochondrial status, redox balance, protein expression, and biogenic amine profiles. Results: Melatonin significantly reduced cell viability, migration, and invasion in both cell lines, with more pronounced effects in MCF-7 cells. At the molecular level, melatonin downregulated key metabolic and hypoxia-related proteins, including GAPDH and HIF-1α, while citrate synthase was selectively reduced in MCF-7 cells, indicating suppression of mitochondrial metabolic capacity. This was accompanied by a reduction in mitochondrial status, reflected by decreased MitoGreen staining. Melatonin also induced redox imbalance, as evidenced by increased lipid peroxidation and protein carbonylation, along with subtype-dependent modulation of antioxidant enzymes. In addition, alterations in biogenic amine profiles were observed, suggesting broader metabolic remodeling. Conclusions: Collectively, these findings demonstrate that melatonin exerts subtype-dependent antitumor effects by targeting metabolic, mitochondrial, and redox pathways, supporting further investigation of melatonin as a potential therapeutic adjuvant in breast cancer, while recognizing that the concentrations used in this study exceed physiological circulating levels. Full article

Background: Background breast features are frequently noted in pathology reports alongside invasive breast cancer but rarely factor into prognosis or treatment decisions. Their relationship to tumor characteristics and patient outcomes remains incompletely characterized. Methods: We conducted a retrospective cohort study of 7603 patients with Stage I–III invasive breast cancer (diagnosed 1991–2022, age < 80 years) from the Joint Breast Cancer Registry in Singapore. Natural language processing (NLP) was applied to 9754 free-text pathology reports to extract co-existing background breast features, with accuracy validated by dual-reviewer assessment of 200 reports. Because background features are most reliably assessed on excision specimens, the primary analytic cohort comprised 3988 patients with available excision pathology reports. Unsupervised hierarchical clustering grouped extracted features into three categories. Associations with tumor characteristics were assessed with multinomial logistic regression and ten-year overall survival by Cox proportional hazards models (median follow-up 9.6 years; 620 deaths). Results: Here, we show that NLP-based extraction of background breast features from routine pathology reports achieves an accuracy of over 90% across features. Lobular neoplasia and benign proliferative changes are associated with less aggressive tumor characteristics, whereas early neoplastic and papillary lesions are more prevalent in HER2-enriched and luminal B tumor subtypes. Benign proliferative changes are associated with better survival in age- and year-adjusted models (hazard ratio 0.91, 95% CI 0.86–0.97), but this association is attenuated after adjustment for stage and subtype. Conclusions: NLP-enabled extraction of background breast features from pathology text is feasible at scale. These features reflect tumor biology but do not independently add prognostic information beyond established clinical variables. Full article

The pituitary gland is an uncommon site of tumor metastasis and is predominantly associated with malignancies of the lung and breast. Metastatic involvement of the pituitary gland in lung cancer (LC) typically indicates advanced disease and is associated with poor prognosis and pituitary insufficiency, which often remains underdiagnosed and significantly affects quality of life and survival. We present four cases of pituitary metastasis (PM) originating from LC, characterized by distinct histological subtypes, variable timing from initial diagnosis, and diverse clinical manifestations. Clinical presentation was heterogeneous: two patients had involvement of both pituitary lobes with multiple pituitary hormone deficiencies, one had anterior lobe involvement with anterior pituitary deficiency following immune checkpoint inhibitor-associated hypophysitis, and one remained asymptomatic. Therapeutic approaches included partial surgical resection followed by radiotherapy in two patients and radiotherapy alone in the other two; all patients continued systemic antineoplastic therapy and received hormone replacement as indicated. Mean overall survival was 7.5 months. PM can occur across all histological subtypes of LC and typically signifies advanced disease with poor prognosis. Early identification and appropriate management of hypopituitarism may improve quality of life and clinical outcomes. Full article

Background: Pathogenic BRCA1 and BRCA2 mutations confer a homologous recombination deficiency that underlies PARP inhibitor sensitivity. While BRCA1 mutation carriers more frequently develop triple-negative breast cancer (TNBC) and BRCA2 carriers hormone receptor-positive (HR+) disease, whether the specific protein domain harboring a pathogenic somatic mutation differs systematically between breast cancer subtypes remains uncertain. Apparent domain enrichment in earlier unfiltered analyses may be confounded by missense variants of uncertain significance (VUSs), which lack clinical actionability. Methods: We assembled three independent breast cancer cohorts via cBioPortal: TCGA-BRCA (brca_tcga_pub2015), METABRIC (brca_metabric), and MSK-CHORD (msk_chord_2024). All somatic BRCA1/2 mutations were mapped to UniProt-annotated functional domains and to Rebbeck-defined breast/ovarian cancer cluster regions (BCCR/OCCR). Per ENIGMA/ACMG guidance, pathogenic mutations (nonsense, frameshift, and canonical splice site) were analyzed inferentially, while missense and in-frame variants—predominantly VUSs—were only reported descriptively. Fisher’s exact tests with Benjamini–Hochberg FDR correction were applied across domain × subtype contingencies. Cohort heterogeneity was assessed via Cochran’s Q and I² statistics; pooled effect estimates were computed using inverse-variance fixed-effects meta-analysis. Results: A total of 394 somatic BRCA1/2 mutations were identified across the three cohorts (BRCA1 n = 166; BRCA2 n = 228), of which 147 (37.3%) met pathogenic criteria. Among 131 pathogenic mutations in HR+/HER2− or TNBC subtypes, 84 (64.1%) occurred in HR+/HER2− disease and 47 (35.9%) in TNBC. Domain-level distributions did not differ significantly between subtypes for any BRCA1 domain (BRCT: TNBC 20.0% vs. HR+ 18.8%, OR = 1.08, 95% CI 0.31–3.78, and FDR-adjusted p = 1.00) or BRCA2 domain (DBD: TNBC 17.6% vs. HR+ 30.8%, OR = 0.48, and FDR-adjusted p = 1.00). Cluster-region analyses (nine Rebbeck BCCR/OCCRs) similarly showed no significant enrichment. Post hoc power analysis indicated that the study could only reliably detect large effects (OR ≥ ~3.0 for the principal BRCT contrast), and formal equivalence testing (TOST) demonstrated equivalence within a prespecified ±20% margin for BRCA1 BRCT (TOST p = 0.031). Heterogeneity across cohorts was minimal (Cochran’s Q = 0.62, I² = 0.0%). Descriptive analyses of VUSs suggested the apparent enrichment of BRCA1 BRCT-localized missense variants in TNBC (31.8% vs. 17.9% in HR+), but this signal did not extend to pathogenic mutations. Conclusions: Within the statistical power available, our three-cohort analysis shows no evidence of large subtype-specific enrichment of pathogenic BRCA1/2 somatic mutations across protein domains or cluster regions; small to moderate effects cannot be excluded. Notably, the majority (64%) of pathogenic mutations occurred in HR+/HER2− disease, underscoring that BRCA1/2 testing should not be deprioritized in non-TNBC subtypes. The apparent BRCT enrichment observed in earlier unfiltered analyses appears to be driven by VUSs rather than pathogenic variants, highlighting the methodological necessity of pathogenicity filtering for clinically actionable inference. These findings provide cohort-scale supportive evidence for emerging clinical guidelines that recommend broader BRCA1/2 testing across breast cancer subtypes. Full article

Triple-negative breast cancer (TNBC), characterized by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, is a highly aggressive molecular subtype with high recurrence and metastasis rates. Due to the absence of reliable molecular targets, surgery combined with chemotherapy remains the mainstay of clinical treatment. In recent years, immunotherapy has provided new strategies for TNBC management. Immune checkpoints are key regulatory molecules that maintain immune homeostasis, and blocking these checkpoints can restore T cell activity and enhance tumor cell killing. Immune checkpoint inhibitors (ICIs) have demonstrated clinical benefit, particularly in combination with chemotherapy for patients with locally advanced or metastatic TNBC. This review focuses on immune checkpoint–based immunotherapy in TNBC, providing an overview from mechanistic insights to clinical applications and emerging therapeutic strategies. In addition to ICIs, we discuss alternative approaches, such as bispecific antibodies, antibody–drug conjugates (ADCs), chimeric antigen receptor T cell (CAR-T) therapy, tumor vaccines, and oncolytic viruses (OVs), highlighting their current research progress and clinical applications in TNBC treatment. Full article

Breast cancer (BC) is associated with metabolic factors that may influence circulating lipids and apolipoproteins. We performed a cross-sectional observational study including 198 women with infiltrating ductal breast carcinoma and 78 cancer-free controls. In the analyzed data, the breast cancer cohort included 39 premenopausal and 44 postmenopausal women without neoadjuvant chemotherapy (NACT), and 35 premenopausal and 54 postmenopausal women exposed to NACT; controls included 63 premenopausal and 52 postmenopausal women. Serum ApoA1 and ApoB were measured by ELISA, and HDL and LDL cholesterol were measured by enzymatic methods. Analyses included two-way ANOVA, Tukey post hoc testing, false-discovery-rate correction, and multivariable linear models adjusted for age and BMI, with HC3 robust sensitivity analyses. In cancer patients, HDL was lower in women exposed to NACT (adjusted β = −8.16, 95% CI −12.61 to −3.71), and ApoA1 differed by menopausal status. Subtype-aware analyses in the available subset did not show independent molecular subtype effects after multiplicity correction. These findings support cross-sectional associations between menopausal status, treatment exposure, and lipid/apolipoprotein profiles, but do not establish causality or prognostic value. Prospective longitudinal studies are required. Full article

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking effective targeted therapies, highlighting the need for new anticancer agents. Natural products remain a valuable source of bioactive compounds with diverse mechanisms of action. In this study, a pyrone glucoside, 7-hydroxymaltol-3-O-β-D-glucoside, was isolated from the methanolic leaf extract of Maerua angolensis and evaluated for its anticancer activity against TNBC cells. Structural elucidation was achieved using NMR and LC–MS analyses. Both the crude extract and the isolated compound exhibited dose-dependent cytotoxicity against MDA-MB-468 cells, with IC₅₀ values of 2.94 and 0.78 µg/mL, respectively, while showing reduced toxicity toward MCF10A normal cells. Mechanistic studies revealed induction of apoptosis, evidenced by activation of caspase-9 and caspase-7 and PARP cleavage. Confocal imaging further demonstrated lysosomal disruption and nuclear morphological alterations consistent with stress-associated cell death. Gene expression analysis indicated minimal involvement of the PI3K/AKT/mTOR pathway. Molecular docking showed favorable binding of the compound to AKT1, PARP-1, and caspase-7, suggesting a multi-target mode of action. ADMET analysis indicated low oral bioavailability but a favorable safety profile. These findings highlight the potential of this compound as a lead for TNBC therapy. Full article

Endocrine therapy is an effective and common treatment strategy for estrogen receptor (ER)-positive breast cancers. However, the development of endocrine resistance, through genetic mutations and epigenetic alterations, in about 40% of treated patients remains a significant therapeutic challenge. Liver X receptors (LXRs) are nuclear receptors that regulate lipid metabolism and cholesterol homeostasis and have been implicated in metabolic reprogramming in breast cancers and other malignancies. We previously identified a novel LXR ligand GAC0001E5 (1E5), with potent antiproliferative activity across breast cancer subtypes. Here, we investigate its mechanisms of action in responsive (MCF-7) and endocrine-resistant (MCF-7-TamR) ER-positive breast cancer cells. Treatment with 1E5 resulted in the downregulation of LXR and its target genes, and significantly reduced ERα expression and the expression of ER-responsive genes. Aberrant expression of androgen receptor (AR) and human epidermal growth factor receptor 2 (HER2), both implicated in endocrine resistance, were downregulated following 1E5 treatment. siRNA-mediated knockdown of LXR expression only partially recapitulated the actions of 1E5, suggesting the involvement of LXR-dependent and independent mechanisms. Collectively, these findings reveal potential crosstalk between LXR and the genetic and epigenetic regulation of pathways involved in endocrine response and alternative signaling mechanisms, highlighting potential targets in endocrine-resistant breast cancer. Full article