Search Results (3,409)

Ultrasound imaging is widely used for early breast cancer screening to enhance patient survival. However, interpreting these images is inherently challenging due to speckle noise, low lesion-to-tissue contrast, and highly variable tumor morphology within complex anatomical structures. Additionally, variations in image characteristics across institutions and devices further impede the development of robust and generalizable computer-aided diagnostic systems. To alleviate these issues, this paper presents a cross-domain segmentation prior guided classification strategy for robust breast tumor diagnosis in ultrasound imaging, implemented through a novel Dual-Stream Diagnosis Network (DSDNet). DSDNet adopts a decoupled dual-stream architecture, where a frozen segmentation branch supplies spatial priors to guide the classification backbone. This design enables stable and accurate performance across diverse imaging conditions and clinical settings. To realize the proposed DSDNet framework, three novel modules are created. The Dual-Stream Mask Attention (DSMA) module enhances lesion priors by jointly modeling foreground and background cues. The Segmentation Prior Guidance Fusion (SPGF) module integrates multi-scale priors into the classification backbone using cross-domain spatial cues, improving tumor morphology representation. The Mamba-Inspired Linear Transformer (MILT) block, built upon the Mamba-Inspired Linear Attention (MILA) mechanism, serves as an efficient attention-based feature extractor. On the BUSI, BUS, and GDPH_SYSUCC datasets, DSDNet achieves ACC values of 0.878, 0.836, and 0.882, and Recall scores of 0.866, 0.789, and 0.878, respectively. These results highlight the effectiveness and strong classification performance of our method in ultrasound breast cancer diagnosis. Full article

Background/Objectives: Although tissue inhibitors of metalloproteinases (TIMPs) are key regulators in breast cancer, their differential expression, clinical relevance, and molecular roles remain unclear. This study aimed to compare the expression patterns of the four TIMPs in breast cancer and evaluate their molecular interactions and associated pathways through an integrated bioinformatic analysis. Methods: The expression of TIMPs and their correlations with MMPs were analyzed using the TCGA PanCancer, cBioPortal, and GEO datasets. Associations between TIMP expression and overall survival were assessed in the TCGA Breast Invasive Carcinoma PanCancer cohort. Pathway enrichment analysis was performed using GO, KEGG, and DAVID. The relationships between immune cell infiltration, stromal cells, and TIMP expression were assessed using the EPIC algorithm. Statistical analyses were performed using R. Results: TIMP1 was the only inhibitor overexpressed in breast tumors and showed significant associations with the Luminal B, HER2, TNBC, and normal-like subtypes, along with a modest increase across stages. TIMP2, TIMP3, and TIMP4 were downregulated in tumors. High expression of TIMP1 and TIMP4 correlated with better overall survival. TIMP1-associated genes were enriched in NF-kappa and PI3K–Akt signaling and actin cytoskeleton components. TIMP2 was linked to Hedgehog and MAPK pathways and actin-related elements. TIMP3 correlated with Hedgehog and PI3K–Akt signaling, DNA damage response, and membrane components. TIMP4 was associated with VEGF, MAPK, PI3K–Akt, DNA damage pathways, and actin organization. TIMP2 showed strong positive correlations with MMP2 and MMP14, while TIMP4 showed negative correlations with MMP1 and MMP9. Interestingly, we found a strong positive correlation between TIMP2 and TIMP3 with ADAM12, as well as between TIMP2 and TIMP3 with ADAM10, and negative correlations with ADAM15. The differential expression of TIMPs favors greater infiltration of immune cells related to tumor progression and poor prognosis in breast cancer patients. Conclusions: TIMPs display contrasting expression profiles and distinct pathway associations in breast cancer. TIMP1 emerges as the only consistently overexpressed inhibitor, while TIMP4 appears as a promising prognostic marker with unique MMP correlations that may influence tumor behaviors. Full article

Obesity is frequently associated with metabolic alterations like hypercholesterolemia and hyperinsulinemia and represents a major risk factor for several diseases, including breast cancer (BC). Insulin signaling, as well as the frequent overexpression of the insulin receptor (IR), play a key role in BC progression. Emerging evidence suggests that the widely prescribed lipid-lowering drugs, named statins, may reduce the risk of recurrence and blunt BC cell proliferation, mainly inhibiting the HMGCR-dependent activation of the mevalonate pathway. In this study, we investigated the effects of simvastatin, atorvastatin and rosuvastatin in BC cells stimulated by insulin. To this end, we used as a BC model system MCF7 cells and naturally immortalized BCAHC-1 cells, which are characterized by high IR-expression levels. Our investigation demonstrates that statins reduce the proliferation and clonogenic capacity of BC cells prompted by insulin treatment. Mechanistically, statins impair the IR-mediated signaling and downregulate the stress-inducible transcription factor NUPR1, a known regulator of cancer progression. Importantly, NUPR1 inhibition blunted the stimulatory action of insulin on BC cells. Consistent with these findings, survival analyses of large cohorts of patients revealed that high levels of NUPR1 are associated with poor BC prognosis. Overall, our results provide novel mechanistic evidence supporting the repositioning of statins in BC, particularly in tumors characterized by elevated IR expression and activity. Full article

Background: Adjuvant tamoxifen reduces recurrence in patients with ER-positive DCIS treated with lumpectomy and radiation, but its benefit after mastectomy remains unclear. Methods: We retrospectively analyzed 287 patients who underwent mastectomy for pure DCIS at Siriraj Hospital between 2008 and 2017. Recurrence risk factors were assessed using log-rank test, and survival probabilities were estimated with Kaplan–Meier analysis. Results: Of 180 patients with hormone receptor (HR)-positive pure DCIS treated with mastectomy, 120 (66.7%) received tamoxifen, while the remaining 60 (33.3%) did not. The median follow-up was 8.07 years (0.05–13.8 years). Sixteen (8.9%) recurrences were identified, with 5 in the tamoxifen group and 11 in non-endocrine-therapy (ET) group. The 10-year recurrence-free survival (RFS) was 94.7% in the tamoxifen group compared with 77.9% in the non-ET group. Patients with HR-positive DCIS treated with tamoxifen following mastectomy had significantly less subsequent breast cancer (HR = 0.178; p = 0.001). Conclusions: Recurrence of breast cancer after mastectomy for DCIS is rare; however, it carries a high mortality rate for those who relapse. Adjuvant tamoxifen after mastectomy demonstrated a significant reduction in the risk of recurrence in ER-positive DCIS. This study supports the decision to prescribe adjuvant ET in patients with DCIS who underwent mastectomy. Full article

Secretory Leukocyte Protease Inhibitor (SLPI) is a conserved serine protease inhibitor expressed on mucosal surfaces, which has multiple functions including anti-protease, anti-microbial and anti-inflammatory properties. SLPI plays critical roles in tissue homeostasis and pathology. Through its anti-protease ability, SLPI safeguards tissues from excessive damage caused by proteolytic enzymes released during inflammation and contributes to extracellular matrix remodeling, thereby influencing the cellular and tumor microenvironment. Furthermore, SLPI expression is implicated in shaping the immune landscape that facilitates tumor progression, and in driving epithelial–mesenchymal transition (EMT). Consequently, it is not surprising that SLPI plays a complex and context-dependent role across various malignancies. It is overexpressed in most cancers such as colorectal, gastric, pancreatic, and breast carcinomas, and this overexpression often correlates with a more advanced and aggressive disease. Conversely, its levels are reduced in head and neck squamous cell carcinoma and hepatocellular carcinoma, where elevated expression may be associated with a more favorable prognosis. This diverse behavior underscores that SLPI function in cancer is tissue-specific and dependent on the functional or pathological state. In prostate cancer, SLPI expression exhibits a bimodal behavior: levels are reduced in the early stages of the disease compared to normal tissues but become significantly upregulated in more advanced and aggressive stages of disease, with significantly higher levels observed in patients with castration-resistant prostate cancer. Elevated SLPI levels in prostate cancer correlate with a reduced prostate-specific antigen (PSA) progression-free survival. In this review, we outline the current evidence regarding the multifaceted functions of SLPI and its expanding role in cancer, focusing primarily on the recently described molecular mechanisms and clinical significance of SLPI in prostate carcinoma. Full article

Human neuroglobin (Ngb) is a globin featuring a disulfide bond (Cys46–Cys55) and a redox-active cysteine residue (Cys120) and plays a dual role in cellular stress responses. In this study, we investigated how wild-type (WT) Ngb and its two mutants, C120S Ngb, in which Cys120 is replaced by serine, and A15C Ngb, which contains an engineered Cys15–Cys120 disulfide bridge, modulate oxidative stress in triple-negative breast cancer (MDAMB231) and hormone receptor-positive breast cancer (MCF-7) cells. In both cell lines, WT Ngb enhanced cell survival under H₂O₂-induced oxidative stress by scavenging reactive oxygen species (ROS) through oxidation of Cys120. In contrast, the C120S and A15C mutants lost this protective capacity and instead promoted apoptosis. Mass spectrometry analysis confirmed the oxidation of Cys120 to sulfenic acid in WT Ngb, whereas both mutants exhibited impaired redox activity, leading to elevated ROS levels, lipid peroxidation, and activation of caspase-9/3. AO/EB staining further revealed that WT Ngb attenuated DNA damage, while the mutants exacerbated apoptosis in both MDAMB231 and MCF-7 cells. These results demonstrate that Cys120 acts as a critical redox switch, dictating whether Ngb exerts cytoprotective or pro-apoptotic effects across different breast cancer cell types. Our findings suggest that WT Ngb may help protect normal tissues during cancer therapy, whereas engineered Ngb mutants could be used to selectively sensitize both triple-negative and hormone receptor-positive breast cancer cells to oxidative damage, offering a novel redox-targeted therapeutic strategy. Full article

Background: Childhood cancers account for approximately 1–2% of all malignancies worldwide, with hematologic cancers representing about 35–40% of pediatric cases. Improved survival has brought increased recognition of both acute and long-term therapy-related complications, including secondary malignant neoplasms (SMNs). Survivors of pediatric hematologic malignancies face a lifelong risk of secondary malignant neoplasms (SMNs), which remain among the most severe late effects of therapy. Methods: We conducted a PRISMA 2020–aligned systematic review of cohort and registry studies evaluating SMNs after childhood hematologic cancers. Databases searched included PubMed, Embase, Web of Science, Scopus, and Cochrane Library. Two reviewers independently screened studies, extracted data, and assessed risk of bias using the Newcastle–Ottawa Scale; disagreements were resolved by a third reviewer. Results: Forty-three studies (>70,000 survivors, median follow-up 5–30+ years) were included. Standardized incidence ratios (SIRs) for secondary malignant neoplasms compared to the general population ranged from 2.0 to 6.0, with absolute excess risks (AERs) of approximately 10–40 per 10,000 person-years. Therapy-related acute myeloid leukemia occurred within 5–10 years, while solid secondary malignant neoplasms (breast, thyroid, central nervous system, sarcomas) emerged after 10–25 years. The highest risks for developing secondary malignant neoplasms were observed among female survivors of Hodgkin lymphoma treated with chest and neck radiotherapy, particularly during adolescence, and among hematopoietic stem cell transplant recipients exposed to total body irradiation or chronic graft-versus-host disease. Conclusions: SMNs are predictable late effects requiring lifelong, exposure-anchored surveillance. Precision survivorship—integrating treatment exposures, transplant conditioning, and genetic predisposition—should guide future screening strategies. Full article

Background: Evidence on the efficacy of alpelisib in combination with fulvestrant after progression on CKD4/6 inhibitors (CDK4/6i) is derived from a single non-comparative prospective study. Conversely, the effectiveness of everolimus plus exemestane on PIK3CA-mutant metastatic breast cancer (BC) after CDK4/6i failure has never been investigated in a prospective study. In this retrospective study, we compared alpelisib plus endocrine therapy (ET) with everolimus plus exemestane in patients with PIK3CA-mutant metastatic BC post-CDK4/6i progression. Methods: We tracked 40 patients treated with alpelisib plus ET and 22 treated with everolimus plus exemestane. We further identified 42 patients who did not harbor PIK3CA mutations (PIK3CA-wild-type group) and received everolimus as a subsequent treatment after progression on CDK4/6i. The timeframe spanned from 1st March 2020 to 30th November 2024. Results: The median progression-free survival (PFS) for the alpelisib group was 4.9 months compared to 4.5 months for the everolimus group [Hazard ratio (HR), 1.22; 95% CI, 0.65–2.28; p-value = 0.53]. The median overall survival (OS) was 9.6 months and 18.3 months for alpelisib and everolimus, respectively (HR, 0.67; 95% CI, 0.25–1.76; p-value = 0.47). Median PFS in the PIK3CA-mutant everolimus plus ET group was 4.5 months (95% CI, 2.8–6.7) compared to 5 months (95% CI, 3.5–6.9) for the PIK3CA-wild-type everolimus plus ET group (HR, 0.77; 95% CI, 0.46–1.29; p-value = 0.32). The most common side effects in the alpelisib group were hyperglycemia (57.5%), rash (27.5%), and anorexia (22.5%), while the most common side effects in the everolimus group were fatigue (40.9%) and stomatitis (27.3%). Conclusion: Our results regarding the efficacy of alpelisib plus ET were inferior to those reported in the current literature. Conversely, outcomes of everolimus plus exemestane were consistent with the current literature, denoting that the combination is an acceptable treatment option for patients with PIK3CA-mutant metastatic BC. Full article

Telomerase is known as a very specific marker of embryonic cells. It is responsible for telomere elongation (bypassing the end-replication problem) and thus supports normal cell division during tissue and organ development. But it is generally absent or very low in most normal adult somatic cells. However, its overexpression in adulthood (due to secondary expression and activity restoration) is commonly known to be associated with cancer. Apart from its canonical function (associated with telomere length restoration), it also carries out various other roles. Its non-canonical activity covers mitochondrial and epigenetic processes. Consequently, it contributes to the cell response to stress and chemotherapeutic drug treatment. A more detailed understanding of these phenomena offers the opportunity to identify new pathways and targets that may serve as critical factors in breast cancer diagnostics and therapy. In this article, we summarize the latest reports on the discovery of telomerase’s nature, including its canonical and non-canonical roles. The manuscript highlights how these mechanisms contribute to tumorigenesis, therapy resistance, and the survival of cancer cells. Understanding these multifaceted mechanisms behind hTERT’s role in (breast) cancer progression and therapy resistance is crucial for developing more effective therapeutic strategies. Full article

Oncofetal reprogramming has recently emerged as a critical concept in translational cancer research, particularly for its role in driving therapeutic resistance across a variety of malignancies. This biological process refers to a pattern of gene expression that is restricted to embryogenesis, but becomes expressed again in a subpopulation of cancer cells. These genes are typically suppressed after embryogenesis, and their aberrant re-expression in tumors endows cancer cells with stem-like properties and enhanced adaptability. The goal of this review is the following: (i) comprehensively examine the multifaceted nature of oncofetal reprogramming; (ii) elucidate its underlying molecular mechanisms, including its regulators and effectors; and (iii) evaluate its consequences for the therapeutic response in different cancer types. We comprehensively integrate the latest findings from colorectal, breast, lung, liver, and other cancers to provide a detailed understanding of how oncofetal programs interfere with tumor response to treatment. Among the candidates, YAP1 and AP-1 have emerged as central transcriptional drivers of this reprogramming process, especially in colorectal and breast cancers. We also explore the distinct expression patterns of oncofetal genes across different tumor types and how these patterns correlate with treatment outcomes and patient survival. Lastly, we propose a dual-targeting therapeutic strategy that simultaneously targets both cancer stem cells and oncofetal-reprogrammed populations as a more effective approach to overcome resistance and limit recurrence. Full article

Objectives: To explore if MRI can monitor treatment and predict outcome in patients with human epidermal growth factor 2 (HER2)-negative breast cancer receiving neoadjuvant chemotherapy (NACT) with or without bevacizumab. Methods: Multiparametric MRI was performed at baseline and after 12 and 25 weeks of NACT. MRI assessment included tumour size, apparent diffusion coefficient (ADC) from diffusion-weighted imaging (DWI), and signal intensity–time curves and vascular volume transfer constant (K^TRANS) from dynamic contrast-enhanced MRI (DCE). The reference standards were pathological complete response (pCR) at the time of surgery, and 10-year recurrence-free survival. Receiver operating characteristics analyses were performed to assess the predictive value of the MRI parameters. MRI findings and outcomes were compared between the treatment groups. Results: Seventy women were included from November 2008 to July 2012, with a median age of 49.5 years and median tumour diameter of 47 mm. Fourteen patients (20.0%) achieved pCR, while eleven (15.7%) had recurrence during the 10-year follow-up. The treatment significantly reduced tumour size, increased ADC, decreased K^TRANS, and shifted the signal intensity–time curves towards more benign shapes. The DCE parameters changed significantly more in the bevacizumab group. In the bevacizumab group, baseline K^TRANS predicted pCR (Area under curve (AUC) = 0.73), but the difference in pCR-rates between the treatment groups was not significant (p = 0.07). Only tumour size and shrinkage at 12 weeks predicted pCR (AUC = 0.71–0.85) regardless of size measuring method. No MRI parameters predicted survival. Conclusions: All MRI parameters reflected treatment response, but no parameter predicted survival or benefit from adding bevacizumab to chemotherapy. Full article

Purpose: A growing body of evidence has emerged on the role of diet for health outcomes in cancer survivors. Patients transitioning to post-treatment care may seek guidance on dietary changes, and summaries of the evidence for dietary patterns recommended by guidelines can support providers in effectively answering questions. Increasing evidence suggests that food choices impact planetary health. Plant-based diets are one eating pattern that may improve patient outcomes and planetary health. Methods: We performed a literature review and used narrative reporting to summarize evidence for plant-based diets and offer specific guidance for breast, colorectal, and prostate cancer patients who are post-diagnosis. Specifically, we reviewed impacts on recurrence, all-cause, and cancer-specific mortality. Results: Increased fibre intake by consuming foods like fruits, vegetables, and whole grains is associated with a decreased risk of breast cancer-specific and all-cause mortality, as well as reduced colon cancer-specific mortality. Replacing refined grains with whole grains is associated with improved disease-free survival for colon cancer survivors. Higher tree nut consumption is associated with improved disease-free survival for breast, colorectal, and prostate cancer survivors. Soy is safe to consume for breast cancer survivors and is associated with a reduced risk of recurrence. Conversely, more Western dietary patterns high in processed meat intake are associated with an increased risk of colon cancer recurrence and prostate cancer mortality. There are also environmental benefits of a shift towards plant-based diets to address the adverse health outcomes associated with climate change and its potential impact on cancer care delivery as previously outlined in a 2024 ASCO policy statement. Conclusions: Based on the best existing evidence, providers can suggest that patients consider plant-based dietary patterns in the post-treatment phase of their cancer care to support health outcomes and planetary health. Full article

Background/Objectives: Breast cancer cells rely on both mitochondrial metabolism and proteostatic mechanisms for cell fitness. The mitochondrial enzyme IDH2 supports redox balance and biosynthesis, while the ubiquitin-proteasome system (UPS) preserves protein quality. This study aimed to determine whether inhibiting IDH2 enhances sensitivity to proteasome-targeting agents across breast cancer subtypes. Methods: A panel of human and murine breast cancer cell lines was treated with the IDH2 inhibitor AGI-6780, alone or in combination with the proteasome inhibitor carfilzomib (CFZ) or the E1 ubiquitin-activating enzyme inhibitor TAK-243. Synergy was evaluated using Bliss scoring. Apoptosis, clonogenicity, and pathway modulation were assessed through Western blotting, colony-formation assays, and reverse-phase protein array (RPPA) profiling. Results: We observed that co-targeting IDH2 and the UPS produced strong synergistic cytotoxicity in multiple breast cancer models, including in triple-negative MDA-MB-231 and 4T1 cells (Bliss > 25). Combination treatments led to pronounced apoptosis, evidenced by cleaved PARP-1 and Caspase-3 cleavage, and a marked loss of clonogenic potential. RPPA analysis revealed significant alterations in key survival and stress-response pathways, including NF-κB, PI3K-p85, Src, and p38-MAPK. Conclusions: Inhibition of IDH2 markedly enhances the cytotoxic effects of proteasome-targeting by disrupting metabolic–proteostatic balance and promoting apoptotic cell death. These findings identify a growth-inhibitory effect that may be leveraged to improve functional dependency in breast cancer, particularly in triple-negative breast cancer, which currently lacks efficient drug treatments. Full article

Background/Objectives: Breast cancer is the most frequently diagnosed malignancy among women and is characterized by marked heterogeneity in treatment response. Metabolic reprogramming, particularly enhanced de novo lipogenesis, represents a hallmark of cancer progression and a promising therapeutic target. Firsocostat, a selective allosteric inhibitor of acetyl-CoA carboxylase (ACC), has previously been investigated in metabolic diseases but has never been evaluated in breast cancer models. This study aimed to assess the antitumor effects of firsocostat on breast cancer cell lines. Methods: We investigated the cytotoxic and metabolic effects of firsocostat in four breast cancer cell lines—MCF7 (luminal A HR⁺), SK-BR-3 (HER2-positive), MDA-MB-231 (triple-negative), and HCC1937 (triple-negative, BRCA1-mutated)—together with the non-tumorigenic MCF-10A line. Dose- and time-dependent responses were evaluated using phase-contrast microscopy for morphological evaluation, Trypan Blue exclusion assays, and MTS-based viability assays. Results: Firsocostat significantly reduced cell viability across all breast cancer subtypes in a concentration- and time-dependent manner, with IC₅₀ values ranging from 80 to 93 µM. In contrast, non-tumorigenic MCF-10A cells were less affected, indicating a selective cytotoxic effect toward malignant cells. Conclusions: Firsocostat exerts robust cytotoxic effects in breast cancer models, identifying it as a promising metabolism-targeting therapeutic candidate capable of selectively impairing breast cancer cell survival by disrupting fatty acid biosynthesis. These results indicate that firsocostat could represent a viable candidate as a metabolic-based therapeutic approach for breast cancer. Given its established clinical safety profile in metabolic diseases, firsocostat warrants further preclinical investigation and supports further mechanistic and preclinical evaluation. Full article

Background: Triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype, characterized by high genomic instability, metabolic stress, and limited therapeutic options. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a promising vulnerability in TNBC, yet its subtype-specific regulatory landscape remains insufficiently defined. Methods: Using transcriptomic (METABRIC, TCGA, GEO) and proteomic (CPTAC) datasets, ferroptosis-related genes were profiled across PAM50 breast cancer subtypes. Differential expression, univariate Cox regression, LASSO modeling, survival analyses, GSEA, and dimensionality reduction (PCA, t-SNE) were applied. A Ferroptosis Index (FI) was calculated using β-coefficients from the Cox/LASSO regression model. Single-cell RNA-seq data was used to map ferroptosis-associated signature across tumor and microenvironmental compartments. Results: Basal-like tumors exhibited the strongest ferroptosis-associated transcriptional shift, characterized by upregulation of ACSL4 and EZH2 and downregulation of AR, GPX4, and CIRBP. Sixteen ferroptosis-related genes were associated with overall survival, forming a ferroptosis-associated signature. The FI was significantly higher in Basal-like tumors, indicating elevated ferroptosis-associated transcriptional state. GSEA revealed enrichment of cell cycle, mitotic, cytoskeletal, and metabolic stress pathways. Single-cell analysis demonstrated expression of ferroptosis markers across cancer epithelial, stromal, and myeloid populations. Conclusions: Basal-like tumors harbor a distinct ferroptosis-associated transcriptional state linked to tumor aggressiveness and poor prognosis. These findings provide a biologically grounded framework for ferroptosis-related stratification and support future functional and translational studies targeting ferroptosis vulnerabilities in aggressive breast cancer. Full article