Immunotherapeutic strategies for triple-negative breast cancer (TNBC) have yielded only modest response rates, severely limiting patients' clinical outcomes. Clarifying the underlying mechanisms to reverse immunotherapy resistance therefore represents a critical unmet need. In this study, we employed the single-cell RNA sequencing (scRNA-Seq) analysis of human TNBC tissues to identify inositol-trisphosphate 3-kinase B (ITPKB) as a central regulator governing cytotoxic T lymphocyte trafficking into the tumor microenvironment (TME). Ectopic expression of ITPKB robustly enhanced the secretion of C-X-C motif chemokine ligand 9 (CXCL9), a critical chemokine required for effective anti-tumor immune responses. Mechanistically, elevated ITPKB activity accelerated the conversion of inositol 1,4,5-trisphosphate (IP3) to inositol 1,3,4,5-tetrakisphosphate (IP4), thereby dampening IP3-driven endoplasmic reticulum (ER) calcium release. Attenuated intracellular calcium ions (Ca2 +) flux, in turn, promoted the recruitment of signal transducer and activator of transcription 1 (STAT1) and nuclear factor-kappa B (NF-κB) to CXCL9 promoter, driving robust CXCL9 transcription. In addition, utilizing a stepwise virtual screening strategy of 3677 compounds, we identified amentoflavone (AMF) as a novel ITPKB agonist-like compound. AMF treatment could stabilize ITPKB by preventing Trim25-mediated K48-linked ubiquitination and degradation. Notably, in 4T1 and EMT6 syngeneic TNBC murine models, ITPKB-overexpressing or AMF administration exhibited markedly enhanced sensitivity to anti-programmed cell death protein 1 (αPD-1) immune checkpoint blockade. Collectively, these results position ITPKB as a therapeutically tractable molecular switch that remodels the tumor immune landscape via Ca2+-dependent transcriptional rewiring. Targeting ITPKB thus represents a promising strategy to overcome immunotherapy resistance and expand the pool of TNBC patients who may benefit from αPD-1-based immunotherapy.

Messenger RNAs (mRNAs) accumulate at centrosomes in mitosis and interphase, yet the mechanisms governing their localization and their functional significance remain poorly understood. Here, we identify a centriolar satellite - RNA-binding protein (RBP) pathway that regulates CEP350 mRNA localization and stability to support centriole overduplication. We find that CEP350 mRNA localizes to centrosomes in S phase in a microtubule (MT)-dependent manner. The RBP, UNK and centriolar satellite protein, CEP131 stabilize CEP350 mRNA and promote its steady-state levels and centrosomal protein accumulation. CEP350 is required for PLK4-induced centriole overduplication but has limited effects on canonical centriole duplication. Disrupting the centriolar satellite - RBP pathway reduces centriole overduplication in triple-negative breast cancer cells, indicating CEP131 and UNK are potential therapeutic targets for reducing centriole overduplication.

IntroductionSOX2, a key pluripotency gene, plays a central role in breast cancer stem cell (BCSC) biology, driving tumor aggressiveness. Although SOX2 dysregulation has been widely studied across various cancers, its specific regulatory mechanisms in breast cancer (BC) remain incompletely elucidated. This study examined the regulatory axis of the SOX2 gene and associated molecular mechanisms underlying BCSC maintenance and prognosis.MethodsThis retrospective cross-sectional study analyzed breast tumor tissues and adjacent normal controls collected consecutively from two tertiary hospitals. SOX2 promoter methylation was assessed using methylation-Specific PCR, and expression of SOX2, DNMT3b, TET3, miR-200b-3p, and TGFβ1 was quantified by qPCR.ResultsAberrant methylation of the SOX2 promoter, linked to increased expression, was observed in the BC cohort. Notably, several samples exhibited a poised promoter state, reflecting an epigenetic configuration associated with stemness. Upregulation of DNMT3b in miR-200b-reduced cells was significantly associated with SOX2 promoter methylation, suggesting a feedback loop modulating methylation dynamics. Additionally, a positive association between deregulated TET3 and TGFβ1 highlights a positive feedback loop in the dynamic tumor microenvironment. SOX2 methylation emerged as a strong prognostic marker, characterized by a low hazard ratio and high diagnostic sensitivity. Its combination with DNMT3b improved specificity (SE = 90%, SP = 79%). Reduced TET3 and miR200b expression correlated with poor outcomes, and their integration with SOX2 formed a tri-gene signature that enhanced patient stratification. Correlation analyses revealed coordinated expression among SOX2, TET3, and TGFβ1, supporting their role in methylome regulation.ConclusionThe findings underscore the clinical significance of this axis and its embedded feedback circuits in shaping BC progression and therapeutic response.

Diagnoses of gynecologic and breast cancers in women may impose emotional and psychological burdens on their partners. Traditional notions of masculinity in Nigeria often discourage men from expressing vulnerability or seeking emotional support. This article explores the impact of a web-based peer support program on redefining masculinity among male partners of women diagnosed with these cancers.

Therapeutic resistance remains a major challenge in cancer treatment, driven by compensatory signaling and stress response pathways that sustain tumor survival. Topoisomerase IIβ-binding protein 1 (TopBP1), a multifunctional scaffold protein with nine BRCT domains, integrates replication stress signaling with oncogenic networks and is frequently overexpressed in aggressive cancers. Its BRCT7/8 domains mediate critical interactions with E2F1, mutant p53, MIZ1, PLK1, and CIP2A, making TopBP1-BRCT7/8 an attractive therapeutic target. Using docking-guided screening and structure-activity relationship-driven optimization, we developed CS18 as a potent and selective BRCT7/8 inhibitor that disrupts oncogenic TopBP1 complexes without interfering with DNA replication. CS18 suppresses MYC transcriptional programs, restores E2F1-mediated apoptosis, and induces mitotic catastrophe. It exhibits broad-spectrum anticancer activity and synergizes with poly(ADP-ribose) polymerase (PARP) inhibitors in multiple cancer types and enhances osimertinib sensitivity in EGFR-mutated non-small cell lung cancer (NSCLC) cells. CS18 demonstrates efficacy in patient-derived breast cancer xenografts and overcomes osimertinib resistance in refractory NSCLC in vivo. These findings establish CS18 as a chemically distinct TopBP1 inhibitor with translational potential to overcome therapeutic resistance and advance precision oncology.

Delays in receiving a breast cancer (BC) diagnosis and treatment continue to be a major public health concern, particularly in environments where financial status, cultural values, and religious beliefs have a significant impact on how individuals react to disease. However, there are still few established, culturally appropriate instruments for assessing Health Belief Model (HBM) constructs and comprehending how they contribute to patient delay. In this study, a protocol for evaluating HBM components and investigating their connection to patient delay among patients with BC in West Sumatra, Indonesia, is presented. A 31-item questionnaire encompassing six HBM domains: perceived risk, severity, benefits, barriers, self-efficacy, and cues to action was used to gather data from 250 BCE patients in this cross-sectional study. Exploratory factor analysis revealed five meaningful latent constructs, and one poorly performing item was removed to strengthen the instrument. Good internal consistency was shown by the final tool (Cronbach's α: 0.809-0.871). Associations between HBM components and patient delay were then examined through logistic regression using crude and adjusted models. The protocol proved practical and feasible in a community setting.

Benzothiazole derivatives have attracted attention for radiopharmaceutical development due to their potential interactions with biological targets associated with breast cancer. In the present study, a novel 99mTc-DTPA-benzothiazole-17 (TDB-17) compound was synthesized, radiolabeled, and preliminarily evaluated for breast cancer imaging research. In silico studies were performed to predict the interaction of the benzothiazole derivative with breast cancer-related biological targets. TDB-17 was synthesized by conjugating 2-aminobenzothiazole with CaNa3-DTPA and subsequently radiolabeled with 99mTc using SnCl2 as a reducing agent. The synthesized compound and radiocomplex were characterized using radio-high-performance liquid chromatography (radio-HPLC), high-resolution mass spectrometry (HRMS), and nuclear magnetic resonance (NMR). The radiolabeling process produced a radiochemical purity of 96.2 ± 1.2%. A preliminary biological evaluation showed that TDB-17 exhibited hydrophilic properties (log P = -1.5 ± 0.2) and time-dependent cellular uptake in MCF-7 cells, reaching 78.4% at 120 min. Biodistribution and gamma-camera imaging studies in normal mice showed predominant accumulation of TDB-17 in the liver, lungs, and spleen, providing initial information on the in vivo distribution of the radiocomplex. Overall, TDB-17 demonstrated favorable radiochemical characteristics and a preliminary biological profile, supporting further investigation of this 99mTc-labeled benzothiazole derivative for breast cancer imaging applications.

Breast cancer metastasis remains the leading cause of disease-related mortality, yet the regulatory mechanisms enabling tumor cells to adapt to distant tissue environments remain poorly defined. Here, we generated a multi-omic resource integrating transcriptomic (RNA-seq) and chromatin accessibility (ATAC-seq) profiles from estrogen receptor-positive primary breast tumors and matched liver and lung metastases obtained from the same patients, including diagnostic and postmortem specimens. This design enabled direct intra-patient comparisons of primary and metastatic regulatory landscapes. We identified extensive reprogramming of chromatin accessibility and gene expression in metastatic lesions relative to primary tumors, indicating widespread regulatory remodeling. Peak-to-gene correlation analysis uncovered thousands of metastasis-associated enhancer-gene linkages, with metastatic samples exhibiting significantly increased enhancer connectivity. These rewired enhancer networks preferentially targeted clinically relevant genes, including RIPK4 , ISYNA1, and RAB3D, which were associated with three or more enhancers in metastases but not in primary tumors. Furthermore, ATAC-seq footprinting combined with gene expression analysis revealed distinct, tissue-specific transcription factor activity profiles in liver and lung metastases, including ESR1, that were not explained by transcription factor expression levels alone. Together, these data provide a resource of metastasis-specific regulatory elements and their cognate transcription factors, revealing new regulatory vulnerabilities that may be therapeutically exploitable. Implications: These findings support a model in which breast cancer metastasis is driven by enhancer regulatory reprogramming, allowing tumor cells to adapt to a variety of microenvironments.