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Due to the heterogeneity of breast cancer (BRCA) and the limited therapeutic efficacy in specific molecular subtypes, identifying new and effective therapeutic targets remains an urgent clinical need. The transcription factor SALL2 has been shown to play distinct roles in tumorigenesis and progression, but its specific role in BRCA remains unclear. Therefore, this study investigates the effects of SALL2 on BRCA progression. SALL2 expression in the TCGA and clinical BRCA tissue samples was analyzed. Cell and animal models were established to validate the effects of SALL2 on BRCA cell proliferation, migration, and tumorigenicity. Molecular experiments were performed to investigate the association between NSUN2 and SALL2 in BRCA and cellular ferroptosis regulation by SALL2. SALL2 is significantly overexpressed in BRCA tissues and cell lines, knocking down SALL2 reduces BRCA cell growth, migration, and tumorigenesis in vitro and in vivo models. The m5C methyltransferase NSUN2, together with the reader protein YBX1, modifies SALL2 mRNA with m5C, which stabilizes the transcript. SALL2 then acts as a transcriptional repressor by binding directly to the promoter region of ACSL4 and inhibiting its transcriptional activity. Suppression of SALL2 activates ferroptotic cell death by lowering the antioxidant defences of GPX4/SLC7A11 and increasing the expression of ACSL4 and COX2 . Ferroptosis inhibitors can reverse the growth-inhibiting effects caused by SALL2 depletion. In BRCA, SALL2 is precisely regulated by m5C RNA methylation modification, further promoting cancer progression by inhibiting cell ferroptosis, suggesting its potential as a prognostic biomarker and a target for therapy.

Ferroptosis induction is a promising triple-negative breast cancer (TNBC) therapy, but current inducers are suboptimal. Nitazoxanide (NTZ), an FDA-approved antiparasitic with anticancer and redox activity, may be repurposed as a ferroptosis inducer, yet its effects and mechanisms in TNBC are unclear. Anti-TNBC effects of NTZ were assessed in MDA-MB-231 and Hs578T cells via viability, clonogenicity, migration/invasion, and zebrafish xenografts. Ferroptosis was evaluated by iron levels, lipid peroxidation, GSH/GSSG, MDA, ROS, and mitochondrial TEM. Mechanisms were studied by docking, western blot, qPCR, apoptosis assay, cycloheximide chase, and pharmacological rescue. NTZ inhibited proliferation, migration, and invasion in vitro and tumor growth in vivo, and induced ferroptosis. Mechanistically, it disrupted iron homeostasis by upregulating TFR1 and downregulating FPN1, causing iron overload and lipid peroxidation, and promoted β-catenin degradation, which transcriptionally suppressed GPX4, weakening antioxidant defense. Both β-catenin stabilization and ferroptosis inhibition reversed these effects. NTZ is repurposed as a ferroptosis inducer for TNBC via dual disruption of iron homeostasis and β-catenin/GPX4 axis, providing a strong preclinical rationale for its therapeutic use. First evidence that the FDA-approved drug NTZ is repurposed as a ferroptosis inducer in TNBC.NTZ triggers ferroptosis by inducing iron overload and suppressing the β-catenin/GPX4 axis.NTZ suppresses TNBC tumor growth in a zebrafish xenograft model at clinically relevant low doses.This work provides a readily translatable strategy for TNBC therapy.

CDK4/6 inhibitors (CDK4/6i) represent the standard treatment for HR+/HER2- ABC. The study assessed the efficacy and safety profiles of CDK4/6i from first-line (1 L) to third-line (3 L) in patients with HR+/HER2- ABC from high-altitude versus low-altitude regions. HR+/HER2- ABC patients who received CDK4/6i were enrolled from four cancer centers in China. A total of 350 patients were eligible for the study, involving 268 from the low-altitude group and 82 from the high-altitude group. In the 1 L, objective response rate (ORR, 23.7% versus 5.3%, p = 0.01), clinical benefit rate (CBR, 88.1% versus 57.9%, p < 0.0001), and median progression-free survival (PFS, 42.1 months versus 15.2 months, p = 0.001) in the low-altitude group were superior to those in the high-altitude group. In the second-line treatment, CBR in the low-altitude group was higher (87.5% versus 48.0%, p = 5.3E-4). The ORR (20.8% versus 4.0%, p = 0.08) and PFS (15.8 months versus 8.2 months, p = 0.11) were not significantly different. In the 3 L settings, no significance was observed in PFS (5.2 months versus 5.8 months, p = 0.45), ORR (16.5% versus 21.1%, p = 0.74), and CBR (47.1% versus 47.4%, p = 1). The incidence of anemia (43.9% versus 28.3%, p = 0.01), ≥grade 3 anemia (9.8% versus 1.9%, p = 3.10E-03), ≥grade 3 thrombocytopenia (9.8% versus 1.9%, p = 3.10E-03), ≥grade 3 ALT (6.1% versus 0.4%, p = 3.10E-03) and AST (7.3% versus 1.9%, p = 0.02) dysfunction occurred more frequently in the high-altitude group. Patients with HR+/HER2- ABC in the high-altitude region experienced inferior survival outcomes and individualized tolerability to CDK4/6i, which may inform scientific research and the management of CDK4/6i in Chinese patients with HR+/HER2- ABC.

One in eight women will develop breast cancer (BC) over their lifetime. Triple-negative breast cancer (TNBC) accounts for up to 20% of BC cases and has fewer treatment options, greater metastatic potential, a higher risk of recurrence, and a poorer prognosis compared to other BC subtypes. Compared to hormone receptor-positive BCs, TNBC has more tumor-infiltrating lymphocytes, a higher tumor mutational burden, and greater programmed death ligand-1 (PD-L1) expression. While these features suggest greater immunogenicity, the balance of the complex TNBC tumor microenvironment (TME) is immunosuppressive. The TME leads to modest and variable effects of immune checkpoint inhibitors (ICI) for TNBC. This review explores the dysfunctional immunological state of TNBC and proposes a multi-modal strategy integrating cryoablation as a source of tumor-associated antigens (TAAs) and immunostimulatory agents to reprogram antitumor immunity. It specifically explores the strategy of combining ICI and immunostimulants with cryoablation as a source of TAAs.

Immunotherapy with immune checkpoint inhibitors (ICIs) has transformed cancer treatment, yet many patients fail to respond, underscoring the need to better understand mechanisms of resistance. One emerging mechanism involves the recruitment of erythroid progenitors and precursors, known as CD71+ erythroid cells (CECs), to the tumor microenvironment. Using murine models of triple-negative breast cancer (TNBC), we investigated the therapeutic effects of curdlan, a β -glucan. We found that TNBC was associated with extramedullary erythropoiesis and expansion of CECs. Unexpectedly, curdlan worsened tumor progression by further increasing CEC abundance. Immunophenotypic analysis revealed a marked expansion of Galectin-3 (Gal-3)+ CECs in both spleen and tumor. Mechanistically, our findings suggest that curdlan-Dectin-1ligation induces Gal-3 shedding from CD11b+cells, enabling its deposition onto CECs. Notably, we discovered that Gal-3 is co-expressed and colocalized with PD-L1 and Dectin-1 on CECs. Importantly, PD-L1 blockade substantially reduced immunosuppressive Gal-3+PD-L1+ CECs, suppressed extramedullary erythropoiesis, and induced pronounced tumor regression. Re-analysis of publicly available scRNAseq datasets further confirmed the abundance of Gal-3+ CECs in human bone marrow. Collectively, these findings identify Gal-3+PD-L1+ CECs as key drivers of an immunosuppressive tumor microenvironment and reveal a previously unrecognized axis through which PD-L1 blockade exerts therapeutic benefit in breast cancer.

Docetaxel (DTX) is one of the commonly used chemotherapeutic agents for breast cancer. Cuproptosis, a newly defined form of cell death, significantly influences tumor progression. This study aims to identify cuproptosis-related long non-coding RNAs (lncRNAs) involved in regulating the sensitivity of breast cancer to DTX. Cuproptosis-related prognostic lncRNAs in breast cancer were identified through integrated co-expression, differential expression, and prognostic analyses based on the TCGA-BRCA cohort. The role of the identified lncRNA AC008406.3 in regulating cuproptosis in breast cancer cells was experimentally verified. The impact of DTX on the induction of cuproptosis was investigated, and rescue experiments were conducted to validate the involvement of AC008406.3 in modulating breast cancer sensitivity to DTX. AC008406.3 was identified as a potential cuproptosis-related prognostic lncRNA in breast cancer, exhibiting high expression in breast cancer samples, which was associated with unfavorable prognostic outcomes. Knockdown of AC008406.3 specifically induced cuproptosis in breast cancer cells, as evidenced by increased intracellular copper levels and downregulation of lipoylated proteins and Fe-S cluster proteins, thereby suppressing cell proliferation, invasion, and migration; conversely, AC008406.3 overexpression elicited opposite phenotypic changes. Notably, DTX induced the occurrence of cuproptosis in breast cancer, whereas AC008406.3 suppressed this process, thereby diminishing DTX efficacy. However, AC008406.3 knockdown synergistically enhanced the anti-tumor efficacy of DTX in inhibiting breast cancer growth. AC008406.3 reduces the sensitivity of breast cancer to DTX by suppressing cuproptosis. Targeting AC008406.3 may represent a potential strategy to sensitize breast cancer cells to DTX.

Chemotherapy affects over 300,000 U.S. breast cancer patients, which disrupts the gut microbiome and induces gut inflammation-an effect hypothesized to drive gastrointestinal side effects (e.g., diarrhea, vomiting) experienced by 50%-80% of patients. Preclinical studies have found causal links amongst chemotherapy-induced gut microbiome disruption, systemic inflammation, and brain-mediated side effects. Therefore, the gut microbiome represents a therapeutic target to attenuate chemotherapy side effects. Because clinical populations are administered multiple chemotherapeutics in combination, a comprehensive understanding of which treatments disrupt the gut microbiome‒blood‒brain axis is lacking. Here, translationally-relevant regimens of four commonly used breast cancer chemotherapies (paclitaxel, cyclophosphamide, cisplatin, and doxorubicin) were given to adult female C57BL/6 mice, and inflammatory, metabolomics and/or bacteriome outcomes were measured in the gut, gut contents, blood, and brain tissues, along with a fatigue and anxiety-like behavioral assessment. Many inter-chemotherapy differences were observed but notable findings include prolonged circulation and central proinflammatory signals by paclitaxel and sustained disruption of the gut microbiome by cisplatin. In contrast, cyclophosphamide and doxorubicin modestly disrupted the gut microbiome‒blood‒brain axis. Taken together, this study systematically identified that paclitaxel and cisplatin most robustly disrupted the gut microbiome‒blood‒brain axis, suggesting that those treated with these drugs may benefit the most from gut-targeted interventions for associated side effects.

This study investigates serum metabolic profiles in breast cancer to identify diagnostic biomarkers and stage-specific metabolites, offering insights for clinical practice. Gas chromatography‒mass spectrometry (GC‒MS)-based metabolomics analyzed serum from healthy controls, patients with benign breast lesions, and malignant breast cancer cohorts. Orthogonal partial least squares discriminant analysis (OPLS-DA) modeling differentiated metabolic signatures between groups, while Spearman's correlation assessed metabolite-stage relationships. Diagnostic performance was assessed through receiver operating characteristic (ROC) analysis. Amino acid metabolism alterations, particularly in alanine, aspartate, and glutamate metabolism, characterized breast cancer. Malignant cases showed elevated glutamic acid and lactic acid but reduced fructose compared to benign lesions, achieving significant diagnostic discrimination (AUC = 0.9757 for glutamic acid, AUC = 0.9583 for lactic acid, AUC = 1.000 for fructose). Glutamic acid demonstrated progressive elevation across health-to-disease continuum (healthy-benign-early-stage-advanced), strongly correlating with the malignancy stage ( ρ = 0.934, p < 0.001) and effectively distinguishing early/late-stage cancers (AUC = 0.9500). Serum metabolomics identified glutamic acid as a dynamic biomarker for breast cancer detection and staging, warranting further mechanistic studies.

Assessment of risk factors of breast cancer in the general population provides insightful information towards prevention of breast cancer. This study aimed to assess the risk factors of breast cancer among women in a community from a resource-limited setting in sub-Saharan Africa. This descriptive community-based cross-sectional study was conducted in Dodoma, Tanzania, from July to December 2020. The study included women aged between 18 and 70 years. The data were analyzed using SPSS program version 25.0. Independent t -test was used to compare the mean age of the participants for the availability of risk factors of breast cancer. A two-tailed p < 0.05 was considered significant. A total of 354 women were analyzed, and the median age was 27.0 (23.0-35.3) years. Only 11.8% ( n = 18) of all the participants did not have any of the risk factors examined. Not engaging in physical activity was the most frequent risk factor which accounted for 68.2% ( n = 242) of all the participants. There were more 60.7% ( n = 215) of the study participants with a low mean age (22.9 ± 3.5) who had more than 5 risk factors compared to 39.3% ( n = 139) of the participants with a high mean age (25.3 ± 9.4) who had more than 5 risk factors, with no statistically significant difference (95% CI = 0.91-2.22, p = 0.31). There is a large proportion of women younger than 40 years in the population of Tanzanian women with many risk factors of breast cancer. This may contribute to the currently observed increase in the incidence of breast cancer in Tanzania for women aged less than 40 years. Therefore, there is an urgency for targeted awareness and screening for breast cancer among younger women in Tanzania so as to increase early detection and diagnosis.

Breast cancer is genetically and histologically heterogenous, and is influenced by a variety of factors, including the tumor microenvironment (TME). The PAM50 subtypes; Luminal A, Luminal B, Normal-like, Basal-like and Her2-enriched, are associated with different tumor phenotypes and overall survival. The quantity and quality of immune cell infiltration in breast tumors play a key role in cancer development and progression and are associated with survival and treatment response. We used multiplex immunohistochemistry, single-cell RNA sequencing, and two deconvolution algorithms to explore the immune landscape across PAM50 subtypes. Immunostaining of CD3 + T cells, tryptase + mast cells, CD20 + B cells, CD68 + CD163 + macrophages, and CD66b + granulocytes revealed marked differences in tumor immune infiltrates according to breast cancer subtypes. Luminal tumors were relatively deprived of T cells and B cells, while exhibiting sparse to moderate amounts of macrophage infiltration. In contrast, Her2-enriched tumors exhibited a moderate immune presence, with sparse to moderate T cell infiltration and moderate infiltration of B cells and macrophages. At the other end of the spectrum, Basal-like tumors stood out for their strikingly rich immune environment and are heavily infiltrated by T cells, B cells, and macrophages. The results from the single-cell and deconvolution analyses confirmed subtype-specific immune microenvironments, which also allowed us to observe increased levels of natural killer (NK) and CD8 + T cells in Her2-enriched and Basal-like subtypes. In conclusion, our findings demonstrate significant differences in the immune tumor microenvironment between the established breast cancer molecular subtypes.

Accumulating evidence suggests that deregulated long non-coding RNAs (lncRNAs) drive breast cancer (BRCA) progression. This study investigated the expression profile and mechanism of PGM5P4 antisense RNA 1 (PGM5P4-AS1) in BRCA. The differentially expressed lncRNAs in BRCA were identified using the GEO dataset. Cancer and adjacent tissues were obtained from BRCA patients. Real-time quantitative polymerase chain reaction was used to quantify the expression of PGM5P4-AS1, microRNA (miR)-3664-5p, and Krüppel-like factor 9 (KLF9). The Chi-squared test was used to assess the clinicopathological correlation of PGM5P4-AS1. Kaplan-Meier curves and Cox regression were used to evaluate their prognostic significance. Cell Counting Kit-8 kits, flow cytometry, and Transwell assays were used to assess cell proliferation, migration, invasion, and apoptosis. Dual-luciferase reporter and RNA immunoprecipitation assays were used to analyze the gene-target interactions. PGM5P4-AS1 downregulation in BRCA was consistently documented across three GEO datasets. In BRCA cancer tissues, both PGM5P4-AS1 and KLF9 were significantly downregulated, whereas miR-3664-5p was noticeably upregulated. A reduction in PGM5P4-AS1 was associated with tumor differentiation, tumor node metastasis staging, and lymph node metastasis. Low PGM5P4-AS1 expression independently predicts poor survival. Further, miR-3664-5p noticeably reverses the suppression of cell proliferation, migration, and invasion, as well as the promotion of apoptosis, induced by PGM5P4-AS1 overexpression. Mechanistically, miR-3664-5p targets PGM5P4-AS1/KLF9 directly, and KLF9 silencing reverses the cellular function inhibition caused by miR-3664-5p downregulation. This study first shows that decreased PGM5P4-AS1 in BRCA patients links to poor prognosis, promotes malignancy via miR-3664-5p/KLF9 axis, offering new therapy and prognosis in sight.

Triple-negative breast cancer (TNBC) is an aggressive subtype with high histological grade and an increased propensity for early recurrence. Early locoregional recurrence within three months of a Patey mastectomy is uncommon, making this case noteworthy and contributing valuable insight into the biological aggressiveness of TNBC and the prognostic role of tumor-infiltrating lymphocytes (TILs). We report the case of a 49-year-old postmenopausal woman followed for TNBC at the Mohammed VI Oncology Center in Casablanca, Morocco, who presented with a rapidly enlarging inflammatory mass along the outer edge of the left Patey mastectomy scar, extending toward the axillary tail, three months after surgery. Histopathological evaluation confirmed a locoregional recurrence of invasive carcinoma of no special type, revealing a 12.2 cm grade III tumor with a Ki-67 index of 40%, hormone receptor-negative/HER2-negative status, and low TILs (10%). The patient received neoadjuvant chemotherapy, followed by surgical excision of the recurrent lesion, radiotherapy and adjuvant chemotherapy consisting of capecitabine, vinorelbine, and gemcitabine, with good tolerance and no evidence of distant metastasis during follow-up. This case underscores the prognostic impact of low TILs and highlights the importance of considering the tumor microenvironment in risk stratification and personalized management of TNBC.

In conditions of increasing workload on organized mammographic screening programs and deficiency of qualified personnel, implementation of auxiliary technologies on the basis of artificial intelligence (AI) acquires special actuality. The results of retrospective cohort study included 100 histologically verified cases of breast cancer (BI-RADS category 6) permitted to evaluate diagnostic efficiency of AI algorithm as compared to independent conclusions of three certified radiologists with length of service more than 10 years. The sensitivity of technology of AI amounted 86%-96%, depending on dichotomization model. The percentage of total coincidence with appraisal of experts varied within the limits 87-91%. The level of concordance, assessed using weighted Cohen's kappa coefficient, came up to κq = 0.76 (95% CI: 0.68-0.83) that corresponds to "good" concordance. In 1%-3% of cases, the AI algorithm identified suspicious findings missed by experts, at that without increasing volume of groundless examinations due to conservative classification of most disputable cases as BI-RADS 3 with ordering dynamic observation. The obtained results confirm clinical applicability of AI technology as standardizing and relieving tool in practical health care, capable to increase sensitivity of screening and to decrease risk of false-negative conclusions without violation of established clinical protocols. В условиях растущей нагрузки на систему организованного маммографического скрининга и дефицита кадровых ресурсов особую актуальность приобретает внедрение вспомогательных технологий на основе искусственного интеллекта. В ретроспективном когортном исследовании, включавшем 100 гистологически верифицированных случаев рака молочной железы, проведена оценка диагностической эффективности алгоритма искусственного интеллекта в сравнении с независимыми заключениями трех сертифицированных рентгенологов со стажем работы более 10 лет. Чувствительность технологии искусственного интеллекта составила 86—96% в зависимости от модели дихотомизации, процент полного совпадения с экспертными оценками варьировал в пределах 87—91%, а уровень согласованности, оцененный с помощью взвешенной каппы Коэна, достиг κq=0,76 (95% ДИ 0,68—0,83), что соответствует «хорошей» согласованности. В 1—3% случаев алгоритм выявлял подозрительные находки, которые пропускали эксперты, не увеличивая при этом объем необоснованных дополнительных обследований благодаря консервативной классификации большинства спорных случаев как BI-RADS 3 с назначением динамического наблюдения. Полученные данные подтверждают клиническую применимость технологии искусственного интеллекта в качестве стандартизирующего и разгружающего инструмента в практическом здравоохранении, способного повысить чувствительность скрининга и снизить риск ложноотрицательных заключений без нарушения устоявшихся клинических протоколов.

Positive surgical margins remain a persistent challenge in breast-conserving surgery (lumpectomy), often necessitating re-excision or additional adjuvant therapies. We investigated a dual molecular targeting strategy that combines fluorescence imaging with photodynamic therapy (PDT), with potential application in improving surgical precision and eradicating residual disease at the margins of surgery. The breast cancer-targeting peptide 18-4 and its cyclic analog c(18-4), which bind the keratin-1 receptor overexpressed in breast cancer cells, were conjugated to Cy5.5 and IRDye78 to generate imaging probes, and to mesopyropheophorbide-a (mPPa) to produce therapeutic PDT probes. Because chlorin-based photosensitizers are highly hydrophobic, a tri-sulfonated water-solubilizing platform was developed to enable intravenous administration of the PDT agents. The resulting probes were evaluated in EMT6 and MDA-MB-231 breast cancer cell lines using confocal microscopy and quantitative fluorescence assays, and in orthotopic murine breast tumor models to assess tumor localization, retention, and therapeutic efficacy. In vitro, targeted probes exhibited enhanced binding relative to untargeted dyes, with cyclic peptide conjugates generally demonstrating stronger uptake than their linear counterparts. In vivo, the dye-peptide conjugate, IRDye78-(18-4) exhibited improved tumor localization and prolonged retention compared with free dye, enabling clear tumor visualization and informing the timing of PDT treatment. The water-soluble PDT probe WS-Lys(mPPa)-c(18-4) produced delayed tumor progression, with complete responses in a subset of treated animals when illumination coincided with peak probe accumulation. Together, these results demonstrate a matched molecular targeting strategy that supports future investigation of fluorescence-guided lumpectomy followed by targeted photodynamic therapy to eradicate residual disease at surgical margins to potentially reduce reoperation rates in the treatment of cancer.

BET family proteins, which regulate disease-related gene expression by coupling chromatin states with transcriptional regulation through recognition of histone acetylation signals, have emerged as critical drug targets in various cancers. Therefore, real-time monitoring of BET protein activity in tumor cells, tissues, and living organisms is of great significance for inhibitor development and related research. Based on our previous work, a series of far-red fluorescent probes targeting the BET family proteins were designed and synthesized, with the aim of establishing a theranostic system that can be applied at both the cellular and tissue levels. Among these probes, L3 exhibited good binding affinity for BET family proteins and demonstrated outstanding performance in tracking target proteins at both cellular and tissue levels. Significantly, L3 facilitated selective imaging of BRD2/3/4 proteins with a clear distinction between malignant and healthy tissues, while also displaying potent in vitro anticancer activity comparable to JQ1(+), by regulating cell cycle- and apoptosis-associated genes. Furthermore, in vivo imaging studies confirmed the potential of this agent for fluorescence-directed tumor excision surgery. Such results position L3 as a multifunctional chemical tool that integrates real-time visualization with therapeutic efficacy for application in breast cancer investigation.

The serine/threonine kinase PAK1 is increasingly recognized as a pivotal regulator of tumor progression and immune evasion in triple-negative breast cancer (TNBC). However, the development of PAK1 inhibitors with both high potency and favorable drug-like properties remains challenging. Herein, we report the design, synthesis, and biological evaluation of a series of novel PAK1 inhibitors guided by a conformation-driven optimization strategy. We identified ZMF-28, a potent PAK1 inhibitor with an IC 50 of 0.02 μM, exhibiting high selectivity in the kinase profiling assay. Notably, ZMF-28 exhibited 10-fold higher cellular antiproliferative activity against 4T1 cells (IC 50 = 0.22 μM) than the clinical candidate FRAX-486, and achieved significant tumor growth inhibition in vivo without overt toxicity, and demonstrated favorable pharmacokinetics. Mechanistically, ZMF-28 directly binds to PAK1 and blocks its kinase activity, thereby downregulating PD-L1 expression and reversing the immunosuppressive tumor microenvironment, representing a dual-action therapeutic strategy for TNBC. These findings establish ZMF-28 as a promising therapeutic candidate for TNBC and highlight the value of conformation-guided design in kinase inhibitor discovery.

Tumor-derived exosomes (TEXs) hold immense promise as biomarkers for cancer diagnosis, but sensitive and accurate identification is hindered by their intrinsic heterogeneity and extreme scarcity. Co-profiling of exosomal protein and microRNA (miRNA) at the single-molecule level may greatly enhance the precision of cancer diagnosis and prognosis. Herein, we present a single microbead-confined dual-mode detection system that selectively captures TEXs for concurrent quantification of protein and miRNA biomarkers. Exosomal proteins are quantified by measuring fluorescence signal concentrated on a single microbead-based enrichment platform. After on-bead lysis, individual miRNA is recognized by the two peptide nucleic acids (PNAs) to form a strict one-to-one correspondence with the intense light-scattering signal of gold nanoparticles (AuNPs), enabling single-molecule counting analysis. Through comprehensive profiling, a panel of four conjoint biomarkers achieve the highest diagnostic accuracy of 98.33%, outperforming any individual markers or alternative combinations. Importantly, this is the first demonstration of a universal PNA modification strategy that harnesses a DNA mediator to prevent AuNPs self-aggregation. This platform can also be adapted to other cancers by simply changing the aptamers and PNAs to target corresponding biomarkers, showing significant potential for advancing exosome-based liquid biopsies and accelerating the development of next-generation clinical diagnostic tools.

Estrogen receptor alpha (ERα) is central to breast-cancer initiation, progression, and endocrine resistance. This narrative review uses a transparent, non-systematic search of peer-reviewed English-language literature published from 2017 through 2025 to integrate ERα structure and isoforms, genomic and non-genomic signaling, post-translational regulation, tumor-microenvironment interactions, heterogeneity, and therapeutic development. The synthesis distinguishes mechanistic, preclinical, and clinical evidence and highlights areas of uncertainty. ESR1 ligand-binding-domain mutations are rare in untreated primary disease but are enriched after endocrine selection in metastatic disease; emerging oral SERDs, ER-directed PROTACs, and biomarker-matched pathway combinations show heterogeneous results across overall and molecularly defined populations. ER-low disease remains a clinically important category requiring confirmation of pathology, integration of tumor biology and disease setting, and individualized use of endocrine and chemotherapy-based strategies. Overall, therapeutic progress increasingly depends on matching ERα-directed interventions to dynamic biomarkers, resistance mechanisms, treatment history, and tolerability rather than assuming uniform benefit across ER-positive disease.

Microtubule-targeting agents remain among the most effective chemotherapeutics for the treatment of cancer. Inspired by the natural tubulin polymerization inhibitor combretastatin A-4 (CA-4), a series of novel thiazolidine-2,4-dione derivatives was designed, synthesized, and evaluated as potential tubulin-targeting anticancer agents. The cytotoxic activities of the compounds were assessed against the MDA-MB-231, while human umbilical vein endothelial cells (HUVEC) were employed to evaluate selectivity. Compounds 2 and 3 emerged as the most active members of the series (IC 50 = 3.60 and 3.71 μM, respectively), accompanied by remarkably high selectivity indices of 49.7 and 51.3. To elucidate their mechanism of action, compounds 2 and 3 were further evaluated in an in vitro tubulin polymerization assay. Compound 3 displayed the strongest inhibitory activity (IC 50 = 1.07 μM), surpassing the reference inhibitor CA-4 (IC 50 = 2.73 μM). Flow cytometric analysis showed that compound 3 induced G 2 /M cell-cycle arrest, increasing the G 2 /M population from 21.8% to 30.8%, and markedly promoted apoptosis, with total apoptotic cells increasing from 0.13% to 43.9% in MDA-MB-231 cells. Molecular docking and MM-GBSA calculations revealed favorable binding within the colchicine-binding site of tubulin, with compounds 2 and 3 exhibiting substantially stronger predicted binding affinities (ΔG = -89.53 and -92.86 kcal/mol, respectively) than CA-4 (ΔG = -70.08 kcal/mol). Molecular dynamics simulations confirmed the stability of the ligand-protein complexes throughout the simulation period, supporting the proposed binding mode. Furthermore, in silico ADME analysis suggested favorable drug-likeness, high predicted oral absorption, and improved pharmacokinetic characteristics compared with paclitaxel. The present study identifies compounds 2 and 3 as promising lead candidate that combines potent and selective antiproliferative activity, strong tubulin polymerization inhibition, and favorable binding characteristics.

Triple-negative breast cancer (TNBC) represents a highly aggressive breast cancer subtype characterized by a paucity of effective therapeutic options. Consequently, the development of targeted therapies constitutes a promising strategy for TNBC treatment. It has been demonstrated that combining CDK12 and PARP1 inhibitors can trigger synthetic lethality in TNBC cells. In the present study, employing a pharmacophore fusion strategy, we designed and synthesized a series of dual-target inhibitors against CDK12 and PARP1. Among them, compound 20b exerted potent inhibition activity against both CDK12 and PARP1 at nanomolar concentrations. It exhibited markedly superior antiproliferative effects compared with single-target inhibitors and effectively reduced pSer2-CTD (Ser2 phosphorylation) and PAR levels in TNBC cells. Furthermore, compound 20b produced robust colony formation inhibitory effects in TNBC cell lines, accompanied by cell cycle arrest and apoptosis induction. The dual-target CDK12/PARP1 inhibitor 20b developed herein represents a novel lead molecule for TNBC drug development.

Triple-negative breast cancer (TNBC) lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), leading to limited clinical treatment options and a poor prognosis. Currently, conventional chemotherapy remains the mainstay of treatment for TNBC patients, but its efficacy is hindered by limited clinical benefits and profound adverse effects, making the search for more effective therapeutic strategies a matter of urgency. Recently, small-molecule inhibitors have achieved significant breakthroughs in TNBC research. Specifically, the abnormal activation of tyrosine kinase (TK) signaling pathways serves as a critical driver of TNBC progression, positioning small-molecule tyrosine kinase inhibitors (TKIs) as a major research hotspot. Therefore, this review systemically delineates the pathogenesis and treatment modalities of TNBC, focusing on the TKIs evaluated in recent clinical trials either as monotherapies or in combination with other therapeutics, such as chemotherapeutic agents, immunotherapies, and antibody-drug conjugates (ADCs). Furthermore, newly developed small-molecule inhibitors are summarized, outlining their enzyme inhibitory activities, anti-tumor activities, and structure-activity relationships (SAR). The involved tyrosine kinase targets encompass VEGFR, EGFR, FGFR, AXL, ACK1, and MET. Given the challenges in TNBC drug development due to the absence of well-defined biomarkers, this comprehensive summary of the latest advances in targeted therapies aims to provide a valuable reference for the future development of individualized and precision treatments for TNBC patients.

Poly(ADP-ribose) polymerase 1 (PARP1) is a key factor responsible for repairing DNA single-strand breaks and maintaining genomic stability. PARP1 inhibitors have achieved remarkable therapeutic efficacy in the treatment of BRCA-mutant breast cancer. However, only a small proportion of breast cancer patients carry BRCA mutations, which limits the indication scope of such agents. Recent studies have demonstrated that protein arginine methyltransferase 5 (PRMT5) inhibitors can enhance the sensitivity of BRCA wild-type tumor cells to PARP1 inhibitors by suppressing the DNA homologous recombination (HR) pathway. In this study, a series of novel PARP1/PRMT5 dual inhibitors were designed and synthesized for the first time. Among them, compound 8I exerted potent inhibitory activity against both PARP1 and PRMT5, and displayed excellent antiproliferative effects on both BRCA wild-type and BRCA-mutant breast cancer cells. Further mechanistic studies verified that 8I could inhibit HR function by down-regulating the expression of BRCA1, BRCA2 and RAD51, thereby triggering enhanced DNA damage and cell apoptosis. Notably, in the BRCA wild-type MDA-MB-231 xenograft tumor model, compound 8I exhibited more potent in vivo antitumor activity than single-agent treatment with the PARP1 inhibitor Olaparib or the PRMT5 inhibitor GSK3326595, and displayed efficacy comparable to the combination of the two agents. In conclusion, this study established a new class of PARP1/PRMT5 dual inhibitors with prominent synergistic antitumor effects, which hold potential for the treatment of breast cancer.

G-quadruplex (G4)-stabilizing ligands are promising tools for inhibiting tumor cell growth in both in vitro and in vivo models. G4 stabilization interferes with DNA replication, leading to replication stress (RS) and DNA damage, and affects gene expression. Clinical development of the telomere-targeting G4 ligand RHPS4 was discontinued due to cardiotoxicity, prompting the synthesis of congeners with retained activity and improved toxicological profiles. In this study, the antiproliferative effects of RHPS4 derivatives were tested in breast cancer cell lines, MCF7, MDA-MB-231, and HCC1937, and compared with non-tumorigenic breast epithelial cells and normal fibroblasts. Among the analogues, compound 190 preferentially inhibited proliferation in MCF7 cells, an effect weakly associated with telomeric DNA damage. Similar to RHPS4, compound 190 induced RS, downregulated CHK1, and reduced ESR1 mRNA and ERα protein levels in a dose-dependent manner. Reduced transcript levels and enhanced ERα degradation support contributions from both transcriptional and post-translational mechanisms, with degradation potentially linked to RS. These effects were also confirmed in endocrine-resistant MCF7-Y537S cells. Together, these findings identify CHK1 and ERα suppression as responses to compound 190 and support further investigation of acridine-based G4 ligands in endocrine-sensitive and endocrine-resistant luminal breast cancer.

While cancer treatment requires a significant time commitment, the objective time spent does not necessarily reflect a patient's perceived time burden. To understand which specific aspects of care are most burdensome, we sought to quantify frustration with time spent on various cancer care-related tasks among individuals receiving treatment for advanced ovarian or metastatic breast cancer. Upon enrolling in a longitudinal study, 83 participants completed a baseline survey regarding frustration with time spent on cancer care tasks. Frustration was measured on a scale of 0 (not at all frustrating) to 10 (extremely frustrating) for cancer care-related activities including travel, waiting, appointments, and logistical tasks. Scores were compared by employment status, dependent status, and distance from the cancer clinic using Wilcoxon rank-sum and Kruskal-Wallis tests. Median frustration scores for most tasks were low, but ranges were wide. Activities associated with the greatest frustration included number of trips to the cancer center, travel time per trip, wait times, and paperwork. Participants receiving disability benefits reported high frustration with nearly all tasks. Additionally, participants with dependents reported greater frustration with the number of trips, paperwork, time off work, and organizing dependent care. Participants living 30+ miles from the cancer center reported more frustration with travel time per trip and arranging transportation. Time-related frustrations in cancer care are not uniform and more heavily impact participants who are on disability, have dependents, or experience geographic barriers. Individualized care coordination and optimized systemic workflows may minimize care-related time burden for these vulnerable populations.

Stage at diagnosis strongly influences breast cancer (BC) prognosis. However, differences in staging systems and incomplete data in European population-based cancer registries (PBCRs) limit international comparisons. We propose a standardized TNM-based stage reconstruction to analyse long-term stage-specific BC survival across Europe. We analysed 714 864 female BC cases diagnosed during 2001-2013 from 23 PBCRs in 14 European countries from the EUROCARE-6 dataset. Stage data were standardized to the seventh TNM edition. Stage was reconstructed into four categories (I-IV). Ten-year relative survival (RS) and 10-year RS conditional on surviving 5 years (CRS 10/5 ) were estimated in the period 2010-2014 using period analysis. Availability of stage information for BC ranged from 75% to 99% across countries. Early-stage disease (I-II) represented 80% of known stages, with higher prevalence of stage I in Northern and Central Europe than in Eastern Europe. Overall, 10-year age-adjusted RS decreased from 97% in stage I to 10% in stage IV. Geographic variation was limited for stage I and marked for other stages, with poorer outcomes in Eastern Europe. CRS 10/5 showed minimal excess mortality after 5 years for stage I but persistent excess mortality for more advanced stages. Younger women had poorer outcomes than those aged 45-54 years. Population-based data on stage for BC confirm the importance of early diagnosis and highlight large disparities in treatment and prognosis across Europe for patients with advanced-stage BC. Improved availability of harmonized stage information at population level is essential for designing and assessing evidence-based cancer control policies.

Acute radiation esophagitis (ARE) is a clinically relevant toxicity occurring in patients with breast cancer receiving post-operative regional nodal irradiation. The present study aimed to develop and evaluate an interpretable machine-learning (ML) model for grade ≥2 ARE. A total of 324 patients were allocated by outcome-stratified random sampling (7:3) to a training set (n=228) and a held-out test set (n=96). A total of six consensus predictors were retained: Pre-existing pruritus, histological grade, body mass index (BMI), diabetes, tumor laterality and the relative esophageal volume receiving ≥30 Gy (RV_V30). In total, 10 ML algorithms were evaluated. Bootstrap internal validation (1,000 resamples) revealed that logistic regression (LR) had the lowest mean optimism among the three preferred candidates (0.027). Final model selection considered bootstrap stability and corrected performance together with held-out discrimination and calibration, model complexity and clinical interpretability. In the held-out test set, LR achieved an area under the curve value of 0.797 (95% confidence interval, 0.706-0.889), a Brier score of 0.179, a calibration slope of 1.258 and a calibration-in-the-large of -0.056. Decision curve analysis revealed positive net benefit relative to treat-all and treat-none strategies across threshold probabilities of 10-66%. SHapley Additive exPlanations identified histological grade, RV_V30 and BMI as the most influential predictors. The final model was implemented as a nomogram and web-based calculator. Overall, the present study demonstrates that this six-feature clinical-dosimetric model may support individualized risk stratification and radiotherapy planning, but prospective multicenter external validation is required before routine clinical use.

Immune checkpoint inhibitors (ICIs) have recently been approved as part of a neoadjuvant therapy plan for triple-negative breast cancer (TNBC). Consequently, the concurrent use of radiotherapy (RT) and ICIs is becoming increasingly common in clinical practice. Combining RT with ICIs may increase the risk of radiation pneumonitis. However, evidence remains limited regarding whether concurrent ICIs administered during postoperative RT increase the risk of radiation pneumonitis in patients with TNBC. The aim of the present preliminary, single-centre, retrospective, hypothesis-generating study was to evaluate the incidence of radiation pneumonitis in patients with TNBC treated with concurrent ICIs and RT. Patients with TNBC, who were treated at Hubei Cancer Hospital (Wuhan, China) between 2022 and 2024, were retrospectively enrolled. The inclusion criteria were receipt of neoadjuvant chemotherapy with or without ICIs, followed by postoperative adjuvant RT. Patients were divided into two groups: Postoperative RT with concurrent ICIs (ICIs-RT) and postoperative RT alone (RT-alone group). Baseline clinical characteristics, treatment responses, RT parameters and follow-up CT scans for the assessment of radiation pneumonitis were documented. The χ 2 test and Student's t-test were used for the statistical analyses. A total of 132 patients with TNBC were enrolled. The pathological complete response rate following neoadjuvant therapy was significantly higher in patients who subsequently received postoperative ICIs-RT than in those who received RT alone (46.7 vs. 22.5%; P=0.01). Of the 132 patients, 30 received ICIs-RT and 102 received RT alone. In the ICIs-RT group, 5 patients received pembrolizumab, 22 received tislelizumab, 1 received camrelizumab and 2 received toripalimab. Follow-up assessments, including contrast-enhanced CT scans, were performed every 3 months for 1 year. The incidence of grade 1 radiation pneumonitis was 63.3% (19/30) in the ICIs-RT group and 46.1% (47/102) in the RT-alone group, with no statistically significant difference between the groups. No grade 2 or higher radiation pneumonitis occurred in either group. Hypothyroidism was observed in 33.3% (10/30) of patients in the ICIs-RT group, which was significantly higher than the 11.8% (12/102) observed in the RT-alone group (P=0.01). The incidence of grade 1 radiation dermatitis was 10.0% (3/30) in the ICIs-RT group and 9.8% (10/102) in the RT-alone group, whereas the incidence of grade 2 radiation dermatitis was 90.0% (27/30) and 90.2% (92/102), respectively, with no significant difference between the groups. In patients with TNBC previously treated with neoadjuvant ICIs, the addition of concurrent ICIs to postoperative RT did not significantly increase the incidence of radiation dermatitis. Regarding radiation pneumonitis, no statistically significant increase was observed; however, a clinically meaningful trend toward a higher incidence of grade 1 radiation pneumonitis cannot be excluded. An increased risk of hypothyroidism was observed, likely attributable to immune-related adverse effects of ICIs. These preliminary findings require validation in larger prospective trials.

Adjuvant radiation therapy (RT) improves locoregional control after breast cancer surgery, but dose prescription remains based mainly on clinicopathologic risk rather than individual tumor radiosensitivity. The radiation sensitivity index (RSI) and genomic-adjusted radiation dose (GARD) provide a framework for biologically guided radiation therapy personalization. In the neoadjuvant setting, however, radiosensitivity measured on the diagnostic biopsy may not reflect the residual disease ultimately targeted by adjuvant radiation therapy. We analyzed matched pretreatment and posttreatment RNA sequencing data from 2 public cohorts of hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer treated with neoadjuvant chemotherapy. The discovery cohort included 16 matched pairs from GSE191127, and the validation cohort included 14 matched HR+/HER2- pairs from GSE309004. The RSI was computed using a 10-gene rank-based model. The ΔRSI was defined as RSI_post - RSI_pre. Immune fractions were inferred using quanTIseq, and the GARD was calculated for START B, RTOG 1005, and FAST-Forward adjuvant radiation therapy schedules. In the discovery cohort, the mean RSI increased from 0.602 to 0.677 after neoadjuvant chemotherapy, with 12 of 16 patients (75%) showing a posttreatment increase. In the validation cohort, the mean RSI increased from 0.489 to 0.593 (Wilcoxon P = . 014), with 11 of 14 patients (78.6%) showing an increase. In the pooled cohort, the mean ΔRSI was +0.089, and 23 of 30 patients (76.7%) showed an increased RSI after chemotherapy (Wilcoxon P = . 005). Higher pretreatment M2 macrophage fraction correlated with a larger ΔRSI. The RSI changes translated into heterogeneous GARD dose modifications across fractionation schedules. Neoadjuvant chemotherapy is associated with a reproducible increase in RSI in HR+/HER2- breast cancer, suggesting that residual tumors may become more radioresistant at the genomic level after systemic therapy. A postneoadjuvant chemotherapy RSI warrants prospective evaluation for individualized adjuvant radiation therapy strategies.

In the OlympiA trial, adjuvant olaparib improved survival in patients with germline BRCA1 / BRCA2 mutations (gBRCAm) and human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (eBC). This analysis presents real-world data from the French-funded early access program for adjuvant olaparib. Eligible adults had gBRCAm and high-risk, HER2-negative eBC, and had received neoadjuvant/adjuvant chemotherapy plus local treatment. Data on olaparib dosing, adverse events (AEs), and health-related quality of life (QoL) were collected during the 12-month treatment period. Between March 2022 and September 2024, 320 treatment access requests were submitted, of which 308 were approved, with treatment for 217 of the 308 patients (70.5%) at a median follow-up of 10.1 months. Triple-negative tumors were reported in 182 of 308 patients (59.1%) and hormone receptor-positive/HER2-negative tumors in 126 (40.9%). Median age was 45 years (range, 24-82). Most treated patients (208 of 217; 95.9%) started olaparib at 300 mg twice daily. Treatment changes occurred in 139 of 217 patients (64.0%), including interruptions (73 of 217; 33.6%) and dose modifications (66 of 217; 30.4%). Treatment-related AEs occurred in 68 of 217 patients (31.3%), serious AEs in 19 of 217 (8.7%), and AE-related discontinuations in 22 of 217 (10.1%). Two non-olaparib-related deaths occurred and no myelodysplastic syndrome/acute myeloid leukemia was reported. QoL data were available for 85 patients at baseline, decreasing to 26 at month 12. Median global health status/QoL score remained stable throughout treatment. Disease recurrence occurred in 5 of 217 patients (2.3%). These real-world findings support adjuvant olaparib as standard-of-care in patients with gBRCAm and high-risk, HER2-negative eBC, with no new safety signals.