Search Results (711)

Background/Objectives: Neoadjuvant therapy (NAT) may remodel the breast-cancer microenvironment. We evaluated paired changes in programmed death-ligand 1 (PD-L1), vascular endothelial growth factor (VEGF), and tumor-infiltrating lymphocytes (TILs) before and after NAT, and associations with the residual cancer burden (RCB) and survival. Methods: This retrospective study included 102 patients with residual invasive breast cancer after NAT: 34 with luminal B-like/HER2-negative, 34 with luminal B-like/HER2-positive, and 34 with triple-negative breast cancer (TNBC). PD-L1 was assessed using the 22C3 combined positive score, VEGF by the cytoplasmic staining intensity, and stromal TILs according to international recommendations. Results: The median tumor size decreased from 2.5 to 1.7 cm (p < 0.001), the PD-L1 CPS (combined positive score) from 6 to 5 (p = 0.039), and the TILs from 15% to 10% (p < 0.001), whereas VEGF shifted toward stronger staining (p = 0.03). In TNBC, the PD-L1 CPS decreased from 10 to 5 (p = 0.003) and the TILs from 20% to 8% (p < 0.001). Biomarkers were not associated with the RCB in the overall cohort. The initial tumor size predicted RCB II/III (OR: 2.60, p = 0.038). The overall survival differed by subtype (p < 0.001). Conclusions: NAT has induced subtype-dependent immune and angiogenic changes, supporting biomarker reassessment in residual disease. Full article

Cancer immunotherapy faces significant challenges in treating “cold” tumors, which respond poorly to current strategies. Breast cancer is a major cause of cancer-related mortality in women and is a representative immunosuppressive cold tumor. The luminal A subtype of breast cancer exhibits an immune-cold phenotype, with MCF-7 cells used as a representative cell model. Here, we identified (3β,5α,8α)-5,8-epidioxyergost-6-en-3β-ol (EEO), isolated from Gymnopilus orientispectabilis, as an inducer of immunogenic cell death (ICD) hallmarks in MCF-7 cells, including cell surface exposure of calreticulin (CRT) and the extracellular release of damage-associated molecular patterns (DAMPs), such as ATP and High Mobility Group Box 1 (HMGB1). These ICD-associated events subsequently promoted CRT-dependent dendritic cell (DC) activation in a co-culture system with bone marrow-derived DCs and MCF-7 cells. Furthermore, surface-exposed CRT enhanced the phagocytosis of EEO-treated MCF-7 cells by DCs, and this phagocytic activity promoted DC maturation, as indicated by increased cell surface levels of the maturation markers major histocompatibility complex class II (MHC II) and cluster of differentiation 86 (CD86). Moreover, CRT knockdown in MCF-7 cells reduced surface CRT exposure following EEO treatment, thereby suppressing DC-mediated phagocytosis and subsequent DC maturation. Taken together, these findings suggest that EEO is a promising candidate for enhancing the antitumor efficacy of existing breast cancer immunotherapies through ICD-mediated DC maturation and converting immunologically cold tumors into hot tumors. Full article

Neoadjuvant chemotherapy (NAC) is the standard of care for locally advanced breast cancer, yet the molecular predictors of pathological response remain incompletely defined, particularly regarding microRNA (miRNA) dynamics. We investigated paired pre- and post-NAC miRNA expression profiles in relation to molecular subtype, residual cancer burden (RCB), and clinical timing parameters. Seven patients with invasive breast cancer (Luminal A n = 3, Luminal B n = 1, TNBC n = 2, HER2+ n = 1) who received NAC (AC-T or TCHP) were included in this pilot study. Small-RNA sequencing (NovaSeq X Plus, CeGaT GmbH, project S17293) was performed on 14 FFPE specimens (7 pre-NAC core needle biopsies, 7 post-NAC surgical specimens). Differential expression analysis used the paired Wilcoxon signed-rank test with Benjamini–Hochberg correction. Spearman correlations assessed associations between miRNA expression, RCB score, and clinical timing intervals. Candidate miRNAs were subsequently annotated using experimentally validated miRNA–target interactions. After filtering (≥ three counts in ≥ three samples), 759 miRNAs were analysed. No miRNA reached strict significance (padj < 0.05, |log₂FC| > 1.0) after multiple testing correction, consistent with the limited statistical power (n = 7). Under exploratory criteria (p < 0.10, |log₂FC| > 0.5), 156 candidate miRNAs were identified: 70 upregulated and 86 downregulated post-NAC. Leading candidates included hsa-miR-139-3p (+2.60), hsa-miR-139-5p (+2.36), and hsa-miR-1323 (+1.55) as upregulated, and hsa-miR-429 (−2.53), hsa-miR-141-3p (−1.79), and hsa-miR-1277-5p (−1.25) as downregulated post-NAC. The single patient achieving the lowest residual disease burden (P3, Luminal B, RCB-I, score 1.32) displayed a distinct pre-treatment miRNA profile, separating from all other pre-NAC specimens on principal component analysis and characterised by higher baseline hsa-miR-139-3p/-5p and lower baseline hsa-miR-429 and hsa-miR-141-3p expression, suggesting that baseline miRNA expression patterns may contribute to differential chemotherapy response. RCB score showed a non-significant positive trend with post-NAC Ki-67 (ρ = +0.71, p = 0.07). This pilot study identifies NAC-modulated candidate miRNAs in breast cancer and establishes a paired FFPE-based small-RNA-sequencing workflow applicable in routine clinical settings. The distinct pre-treatment profile of the single best responder generates the testable hypothesis that baseline expression of tumour suppressor miRNAs of the miR-139 family, together with low miR-200-family expression, may track chemosensitivity. As no candidate reached statistical significance after multiple testing correction and none has been validated in an independent cohort or by an orthogonal method, all findings are exploratory and hypothesis-generating. The results support larger prospective validation studies examining miRNA signatures as predictive biomarkers of NAC response across breast cancer molecular subtypes. Full article

Immunohistochemistry (IHC) of ER, PR, HER2, and Ki67 are established prognostic and predictive markers in breast cancer. Gene expression assays such as PAM50 and Oncotype DX are increasingly used for molecular subtyping and recurrence risk calculation. The APIS Breast Cancer Subtyping Kit (BCSK) quantitatively measures the mRNA expression of these markers (ER, PR, HER2, and Ki67) and includes a novel four-gene BCSK Proliferation Signature (PS) designed for subtype classification and risk stratification. This exploratory retrospective cohort study compares the BCSK with established molecular assays in an age-stratified cohort. We aimed to compare BCSK subtype classification in distinguishing Luminal A versus Luminal B subtypes with IHC and with PAM50. We have also aimed to assess correlations between the BCSK PS and the Oncotype DX Recurrence Score (RS) as well as the PAM50 Risk of Recurrence (ROR) score in patients stratified by age (<65 versus ≥65 years). Formalin-fixed, paraffin-embedded (FFPE) tumor specimens from 59 patients with ER+/HER2− breast cancer (33 < 65 years, 26 ≥ 65 years), diagnosed between 2020 and 2022 at the Cantonal Hospital Baselland and University Hospital Basel, were analyzed using IHC, BCSK, and PAM50 (Prosigna^®). All patients received adjuvant therapy and had ODx scores available. Patient, disease and treatment characteristics were compared between age groups using the Fisher exact test. We assessed concordance in luminal subtype classification across IHC, BCSK, and PAM50 assays pairwise and stratified by age groups descriptively. We used Spearman’s rank correlation to examine associations between BCSK PS, RS, and ROR. Differences between age groups regarding PS were analyzed using the Mann–Whitney U test. In the ≥65-year cohort, subtype classification concordance between the BCSK and PAM50 was higher (84.6%) than in those aged <65-years (60.6%). In patients aged <65 years, the PS was significantly correlated with both RS (ρ = 0.5745, p < 0.0005) and ROR (ρ = 0.391, p = 0.024), whereas RS and ROR were not significantly correlated. In patients ≥65 years, PS correlated significantly with ROR (ρ = 0.603, p = 0.001), while there were no significant correlations between PS and RS (ρ = 0.134, p = 0.514) and between RS and ROR (ρ = 0.149, p = 0.466). Median PS values did not significantly differ between age groups (0.589 versus 0.602, p = 0.97). In this exploratory retrospective age-stratified analysis, the BCSK demonstrated descriptive concordance with PAM50 subtype classifications, especially in patients aged ≥65 years. PS showed significant but moderate correlation with the established molecular recurrence scores RS and ROR, however these differed across age groups. Our findings should be considered hypothesis-generating because this study did not include outcome metrics and was based on a relatively small cohort. Larger prospective studies incorporating clinical outcomes are necessary to determine the diagnostic and prognostic utility as well as comparative cost-effectiveness of the BCSK and its utility across age groups. Full article

Background/Objectives: Breast cancer exhibits substantial molecular heterogeneity, resulting in diverse therapeutic vulnerabilities and limiting the efficacy of single-agent therapies. Although multi-target strategies may offer improved therapeutic benefit, the systematic identification of synergistic higher-order target combinations remains challenging. This study aimed to identify and validate effective higher-order target combinations for heterogeneous breast cancer. Methods: DeepMDS, a previously developed deep learning-based multi-compound synergy prediction model, was used to prioritize candidate target combinations for breast cancer. Exhaustive two-target and three-target combinations were ranked in the gene-expression contexts of ER-positive luminal-like MCF-7 and triple-negative MDA-MB-231 breast cancer cells. The top-ranked target combinations were evaluated using single, pairwise, and triple small interfering RNA (siRNA) perturbations. Representative inhibitors were subsequently assessed in fixed-ratio combinations in MCF-7, MDA-MB-231, and 4T1 cells and in a 4T1 syngeneic mouse experiment. Results: BIRC5-NAMPT-TOP1 ranked first in both cell lines. Triple siRNA co-transfection targeting BIRC5, NAMPT, and TOP1 produced the strongest antiproliferative effects, with inhibition rates of 62.94% in MCF-7 cells and 55.62% in MDA-MB-231 cells. The corresponding inhibitors, LQZ-7I, FK866, and topotecan, exhibited synergistic antiproliferative activity at multiple molar ratios, with combination index values below 1. The optimized 2.5:10:1 molar ratio showed strong synergy in MCF-7, MDA-MB-231, and 4T1 cells, with combination index values of 0.26, 0.19, and 0.15, respectively. In tumor-bearing mice model, the triple-inhibitor regimen achieved a tumor inhibition rate of 62.05%. Topotecan-containing groups showed hematological alterations, whereas no statistically detectable elevations were observed in the measured terminal serum hepatic or renal biomarkers. Conclusions: The BIRC5-NAMPT-TOP1 combination showed reproducible phenotypic activity in the tested genetic and pharmacological models. These findings support the use of DeepMDS as a hypothesis-generation tool for higher-order target prioritization. Full article

Background/Objectives: Serum cancer antigen 15.3 (CA 15.3) is frequently measured in advanced breast cancer, but its prognostic significance after adjusting for established clinical factors remains incompletely characterized in Latin American populations. We evaluated the association of baseline CA 15.3 with metastatic burden and overall survival (OS) in hormone receptor-positive/HER2-negative advanced breast cancer and descriptively explored baseline/follow-up patterns. Methods: We retrospectively evaluated 127 women treated at a Peruvian public oncology institution between 2018 and 2024, with CA 15.3 levels ≥32.4 U/mL being considered elevated. Baseline associations were assessed using multivariable logistic regression, and OS was evaluated using Kaplan–Meier estimates and Cox proportional hazards regression adjusted for age, ECOG performance status, de novo versus recurrent disease, luminal subtype, first-line treatment, number of metastatic sites, and metastatic site. Results: Baseline CA 15.3 was elevated in 41/127 patients (32.3%) and was independently associated with postmenopausal status (OR: 3.27; 95% CI, 1.33–9.03; p = 0.014) and ≥2 metastatic sites (OR: 2.72; 95% CI, 1.24–6.10; p = 0.013). Median OS was 55 months (95% CI, 43–78), while elevated baseline CA 15.3 was associated with shorter OS (41 vs. 65 months; log-rank p = 0.024) and remained independently associated with shorter OS after multivariable adjustment (adjusted HR: 3.42; 95% CI, 1.63–7.19; p = 0.001). Conclusions: Elevated baseline CA 15.3 was associated with greater metastatic burden and shorter OS, and baseline/follow-up patterns were exploratory because the sampling was not standardized. Thus, CA 15.3 should be interpreted as an adjunct to clinical and radiological assessment. Full article

Background: The growing awareness of breast cancer’s molecular diversity has not changed the technical foundations of surgery itself, but it has profoundly reshaped how surgeons think about surgery. Rather than molecular biology prescribing specific surgery, it is the surgeon’s interpretation of biological behavior—tumor subtype, genomic risk, treatment responsiveness—that influences surgical timing, extent, and feasibility. This is particularly important in the developing world, where mastectomy continues to be the default surgery, not always because it is required, but because biological nuance is underutilized in surgical planning. This review integrates existing evidence, guidelines, and real-world clinical experience to show how a surgeon who understands tumor biology can meaningfully expand safe breast conservation, de-escalate axillary surgery, and align operative choices with systemic therapy. In essence, molecular biology becomes a lens through which surgeons can practice more personalized, precise, and less invasive surgery, without compromising oncologic safety. Recent findings: We present evidence-based algorithms focusing on Luminal A, Luminal B, HER2-positive, and triple-negative subtypes, while discussing the nuances of multifocal and multicentric disease, metaplastic histologies, and discordant lesion management. The review addresses axillary management in the molecular era, specifying the appropriateness of sentinel lymph node biopsy, targeted axillary dissection, or completion axillary dissection, and how subtype-specific nodal responses to neoadjuvant therapy can guide de-escalation strategies. Through clinical vignettes, we exemplify how molecular integration into surgical planning can modify clinical courses, enabling oncoplastic conservation in downstaged tumors and justifying definitive resection in chemo-resistant cases. We examine the implications of germline and somatic genetic testing on surgical decision-making, particularly in relation to BRCA1/2 and PALB2 mutation carriers, alongside ethical and practical counseling considerations. Additionally, we review emerging biomarkers—such as circulating tumor DNA and immune and radiomic signatures—and propose research priorities for their incorporation into surgical trials. Conclusions: Effective implementation necessitates enhanced surgeon education, standardized assays, and multidisciplinary coordination to promote equitable access, consistent utilization of biology-driven algorithms, and rigorous quality oversight. This review furnishes breast surgeons with a pragmatic framework for translating molecular knowledge into multidisciplinary, patient-centered care pathways that optimize oncological safety, aesthetic outcomes, and overall quality of life. Full article

Background/Objectives: Breast cancer is the most frequent malignant neoplasm in women and presents marked biological heterogeneity. The androgen receptor (AR) has emerged as a biomarker with important prognostic and therapeutic implications, its effect varying according to the molecular subtype. The objective of this study was to analyze AR expression in breast carcinoma samples and its relationship with the different molecular subtypes and clinicopathological variables. Methods: An observational, descriptive, cross-sectional, and prospective study was conducted based on the immunohistochemical analysis of 215 formalin-fixed, paraffin-embedded breast carcinoma samples. AR expression was digitally evaluated as the percentage of positive tumor cells after incubation with an anti-AR monoclonal antibody. Results: A high frequency of AR expression was demonstrated in the cohort, with a median of 53.3%. There were statistically significant differences between molecular subtypes (p < 0.001), detecting greater expression in luminal tumors and markedly low levels in triple-negative breast cancer (TNBC) (median 0.41%). A significant negative correlation was evidenced between AR expression and the Ki-67 proliferation index (ρ = −0.272; p < 0.001), both in the overall sample and in the TNBC subgroup. Conclusions: The androgen receptor is associated with specific molecular subtypes and lower tumor proliferation, suggesting a less aggressive phenotype and supporting its role as a biological biomarker and potential therapeutic target in the management of breast cancer. Full article

Natural Killer (NK) cell-mediated immunosurveillance is a cornerstone of anti-tumor defense, yet its efficacy can be compromised by common clinical medications. Paracetamol (APAP) and metformin (MET) are widely used for pain and metabolic management in cancer patients, but their unintended effects on the immune–tumor interface remain poorly understood. MCF-7 breast cancer cells (Luminal A subtype) were treated with APAP or MET and co-cultured with primary expanded NK cells (CD3⁻CD56⁺CD16⁺). We evaluated cell proliferation, cell cycle distribution, and the enrichment of the CD44⁺CD24⁻ cancer stem-like cell (CSC-like) subpopulation. Transcriptional changes in immune checkpoints (PD-L1/L2), stress ligands (MICA/B), and costimulatory molecules CD80/86 were quantified via RT-qPCR. Despite inhibiting MCF-7 growth (IC₅₀ at 48 h: 11.86 mM for APAP; 21.11 mM for MET), both drugs induced a “therapeutic paradox” by promoting an immune-evasive phenotype. APAP and MET significantly enriched the CD44⁺CD24⁻ CSC-like subpopulation to 75.31% and 68.31%, respectively, compared to 11.00% in controls. Molecular analysis revealed a robust upregulation of PD-L1 (19.9-fold by APAP) and PD-L2 (16.4-fold by MET), alongside increased CD80/86 and MICA/B transcription. Consequently, drug-treated cells exhibited marked resistance to NK-mediated apoptosis and necrosis. NK cells preferentially eliminated non-stem cells (non-CSCs), inadvertently further concentrating the highly resistant CSC-like subpopulation. Additional experiments revealed that APAP directly impaired NK-cell survival and reduced the proportion of CD3⁻CD56⁺ cells, whereas MET exerted minimal effects on NK cells, suggesting distinct mechanisms underlying the observed reduction in NK-mediated cytotoxicity. Under the experimental conditions employed in this study, APAP and MET were associated with reduced susceptibility of MCF-7 cells to NK-mediated killing through distinct but partially overlapping mechanisms, including CSC-like enrichment and transcriptional activation of immune-evasion pathways. Although these findings were obtained in a mechanistic in vitro model using supra-physiological drug concentrations, they identify potential mechanisms that warrant further validation in physiologically relevant experimental systems and in vivo models. Full article

Phosphatidylinositol 5-phosphate 4-kinase type 2 alpha (PIP4K2A) is a key oncogenic driver that regulates the PI5P/PIP2 axis to promote metastatic migration in breast cancer. This study aimed to investigate the therapeutic potential of a crude extract from Tamarix aphylla against breast cancer progression and identify its primary active constituents. The crude extract was initially evaluated against MDA-MB-231 and MCF7 breast cancer cell lines using wound healing assays. Bioassay-guided isolation and screening were deployed to isolate individual components, and the most potent lead compound was structurally characterized using preparative HPLC and FTIR. To analyze its interaction with PIP4K2A, in silico molecular docking, MM/GBSA calculations, and 200 ns molecular dynamics simulations were conducted. In vitro validation was subsequently performed via dose-dependent cytotoxicity assays, scratch assays, single-cell tracking, and RT-qPCR expression analysis. Quercetin was identified as the most potent lead inhibitor against PIP4K2A. Computational modeling revealed that quercetin binds tightly within the PIP4K2A ATP-binding pocket, yielding a superior binding affinity of −10.77 kcal/mol and enhanced thermodynamic stability (ΔGMM/GBSA = −42.6 ± 2.1 kcal/mol) compared to the native ligand (ΔG MM/GBSA = −23.3 ± 1.8 kcal/mol). Molecular dynamics simulations confirmed an induced-fit structural transition that locked the complex into an ultra-stable conformation within a deep global energy minimum basin (−10.8 kcal/mol). In vitro assays demonstrated dose-dependent cytotoxicity, with aggressive triple-negative MDA-MB-231 cells exhibiting higher sensitivity (IC₅₀ = 82.23 µg/mL) than luminal MCF7 cells (IC₅₀ = 97.14 µg/mL). Furthermore, scratch and single-cell tracking assays showed a profound suppression of migration speed and wound closure (reduced to ~40%), while RT-qPCR revealed a near-complete transcriptional knockdown of PIP4K2A mRNA expression (down to 0.025-fold). Collectively, these findings elucidate a unique dual-action mechanism for Tamarix aphylla-derived quercetin—characterized by both direct competitive enzymatic inhibition and downstream transcriptional silencing—positioning it as a promising therapeutic scaffold for targeted anti-metastatic breast cancer interventions. Full article

Background/Objectives: Vitamin D deficiency is commonly observed in patients with breast cancer and may affect disease course and treatment outcomes. The determinants of vitamin D status in this population remain incompletely understood, particularly with respect to lifestyle, psychosocial, and tumour-related factors. The aim of this study was to identify environmental and clinical factors associated with serum 25-hydroxyvitamin D [25(OH)D] concentrations in women with breast cancer, with particular emphasis on dietary patterns, psychological distress, sleep quality, and tumour molecular subtype. Methods: A cross-sectional observational study was conducted among 101 women with histopathologically confirmed invasive breast cancer, recruited at the St. John of Dukla Oncology Centre of the Lublin Region (COZL) in Lublin, Poland, between 2018 and 2019. Serum 25(OH)D concentrations were measured by electrochemiluminescence immunoassay (ECLIA; Roche Diagnostics) within 2–8 weeks after surgical treatment. Clinical and lifestyle data were collected using standardised questionnaires and medical records. Dietary patterns were assessed with the KomPAN questionnaire (pro-healthy diet index pHDI-10 and non-healthy diet index nHDI-14). Psychological distress was measured with the Distress Thermometer. Multiple linear regression with backward stepwise elimination was applied to identify factors independently associated with of 25(OH)D concentration. Results: Insufficient vitamin D status (25(OH)D < 30 ng/mL) was found in 56.4% of participants. The multivariable regression model was statistically significant (F(6,92) = 15.298; p < 0.001), explaining 49.9% of the variance in 25(OH)D concentrations. Factors independently associated with lower 25(OH)D included higher BMI (b = −0.715; p = 0.005), sleep disturbances (b = −6.257; p = 0.020), higher psychological distress score (b = −2.263; p < 0.001), and luminal B versus luminal A subtype (b = −5.909; p = 0.025). A higher pro healthy diet index (pHDI-10) was independently associated with higher 25(OH)D (b = 0.245; p = 0.040). Conclusions: Vitamin D status in patients with breast cancer is shaped by complex interactions among modifiable lifestyle factors and tumour characteristics. Targeted interventions addressing diet quality, psychological well-being, sleep health, and weight management may improve vitamin D status in this population. The association between molecular subtype and 25(OH)D concentrations warrants further prospective investigation. These findings should be interpreted with caution, as vitamin D supplementation and direct measures of sun exposure—both established determinants of 25(OH)D—could not be included as covariates and may account, at least in part, for the associations reported. Full article

Background: Germline PALB2 variants are associated with hereditary breast cancer risk, but their clinical impact in Central Asian populations remains largely uncharacterized. This case study aims to evaluate the clinical significance of PALB2 variants in two Kazakh women with early-onset breast cancer. Methods: Molecular genetic testing identified germline PALB2 pathogenic variants (NM_024675.4:c.18_22delGAAGC and NM_024675.4:c.1034T>G) in two Kazakh women with early-onset invasive ductal carcinoma. Clinical courses, treatment responses, and outcomes were followed. Results: Neither patient had a reported family history of breast or other malignancies. Patient 1, a 26-year-old pregnant woman, was diagnosed with stage IIIB luminal B, HER2-negative invasive ductal carcinoma and received neoadjuvant chemotherapy, radical surgery, radiotherapy, endocrine therapy, and subsequent treatment for metastatic disease. Despite an initial response, she developed extensive skeletal metastases and died from metastatic breast cancer. Patient 2, a 33-year-old woman, presented with de novo stage IV luminal B, HER2-negative invasive ductal carcinoma with hepatic metastases. Following multimodal treatment, including chemotherapy, surgery, radiotherapy, endocrine suppression, and systemic therapy for disease progression, she experienced further metastatic spread and ultimately died from breast cancer-related complications. Conclusions: Both patients exhibited aggressive clinical courses characterized by early disease onset, metastatic progression, and poor outcomes despite comprehensive treatment. These cases highlight the potential clinical significance of germline PALB2 variants in apparently sporadic breast cancer and underscore the importance of genetic testing, risk assessment, and genetic counselling in young breast cancer patients, particularly in underrepresented. Full article

Estrogen receptor (ER)-positive breast cancer (BrCa) accounts for two-thirds of all BrCa cases worldwide. Therefore, ER-targeted endocrine therapy is the standard treatment for this disease. There has been a recent trend towards developing combination therapies using molecularly targeted drugs to improve outcomes. This study aimed to identify therapeutic targets demonstrating efficacy when combined with fulvestrant (a selective ER downregulator/degrader). We generated microRNA (miRNA) signatures from fulvestrant-treated MCF-7 cells by RNA sequencing. From the signature, we evaluated miR-374b-5p because its expression was elevated by fulvestrant treatment in MCF-7 cells. Also, in expression analysis by subtype of BrCa patients, miR-374b-5p expression was suppressed only in luminal BrCa. Ectopic expression assays revealed that miR-374b-5p attenuated the malignant phenotypes of MCF-7 cells. We searched for genes regulated by miR-374b-5p and discovered that 11 (NEK2, NUF2, HMMR, DEPDC1B, FOXM1, ELOVL6, KIF20A, NCAPH, CENPK, FAM83D, and KIAA0101) are closely involved in BrCa molecular pathogenesis. Among these target genes, we focused on forkhead box M1 (FOXM1), a transcription factor regulating cell cycle progression and division. Notably, combination therapy with fulvestrant and a FOXM1 inhibitor significantly suppressed MCF-7 cell proliferation. From the miRNA signature established in this study, we identified antitumor miR-374b-5p and its target genes and used these findings to explore candidate drugs with potential efficacy when combined with fulvestrant. Full article

WWOX and HIF1A are linked to hypoxia-driven metabolic and immune modulation in cancer. We examined whether the WWOX/HIF1A expression ratio acts as a context-dependent molecular integrator across breast cancer (BRCA) subtypes and ovarian carcinoma (OV). We analyzsed TCGA RNA-seq and clinical data from BRCA (n = 390) and OV (n = 228), using neoplasm cancer status as a proxy for disease-free survival (DFS). Patients were stratified by subtype-specific WWOX/HIF1A ratio cutpoints for exploratory Kaplan–-Meier analyses, and the ratio was also modelled as a standardizsed continuous covariate in Cox regression. Transcriptomic, pathway, immune-cell and hormone-related profiles were examined in relation to ratio status, with all multivariable and cutpoint-based findings treated as hypothesis-generating. The WWOX/HIF1A ratio does not act as a uniform or strongly predictive prognostic marker but instead delineates distinct biological states whose association with DFS is modest, context-dependent and statistically fragile in TCGA. Higher ratios are linked to more favourable DFS only in basal-like and HER2-enriched BRCA, together with oxidative phosphorylation, ribosomal and reduced ADAM10-linked Notch and monocyte/macrophage signatures. In luminal A BRCA and OV, lower ratios are linked to relatively favourable DFS and coincide with cytokine/JAK–STAT signalling, cytotoxic immune signatures and coordinated metabolic–endocrine programmes, whereas luminal B shows mixed immune and metabolic patterns. In this TCGA-based analysis, the WWOX/HIF1A ratio functions as a context-dependent molecular index of hypoxia, immune and hormone-related states rather than a strong, generalisable DFS predictor. The observed subtype-specific survival trends (high-ratio favourability in basal/HER2, low-ratio favourability in luminal A,B and OV) are non-significant and exploratory, and all ratio-based survival patterns require confirmation in independent cohorts and functional studies. Full article

Background/Objectives: PgRMC1 is a progesterone-binding protein often overexpressed in breast cancer, correlating with tumor progression and chemoresistance. Identifying predictive markers for neoadjuvant chemotherapy (NAC) response is crucial for guiding therapeutic decisions. This study examines PgRMC1 expression in breast cancer tissues and its correlation with clinicopathological characteristics and NAC response. Methods: PgRMC1 expression in normal and cancerous breast tissues was evaluated via immunohistochemistry (IHC). Expression of ER, PgR, HER2, AR, and PGRMC1 mRNA was determined by qPCR in 112 patients. A separate 44-patient neoadjuvant chemotherapy (NAC) cohort was assessed for intrinsic subtypes (pretreatment biopsies) alongside PgRMC1 IHC expression and pathological response (post-NAC surgical specimens). In vitro chemoresistance and qPCR analyses were performed in breast cancer cell lines following PgRMC1 overexpression or siRNA-mediated knockdown. Results: PgRMC1 expression was detected in breast cancer tissue, while no immunoreactivity was observed in normal breast tissue. PGRMC1 mRNA expression levels were significantly higher in luminal and HER2 subtypes. In the distinct cohort of patients treated with NAC, those with a poorer pathological response had significantly higher PgRMC1 expression than those with a good response. In vitro, forced overexpression of PgRMC1 in two breast cancer cell lines, MCF7 and MDA-MB-468, significantly reduced chemosensitivity. Overexpression of PgRMC1 modulated the expression of epithelial and differentiation markers, including CDH1, AR, KRT19, and GATA3. Conclusions: PgRMC1 may contribute to chemoresistance and serves as a candidate biomarker for assessing neoadjuvant chemotherapy sensitivity. Full article