Triple-negative breast cancer (TNBC) presents a formidable therapeutic challenge due to its aggressive behavior, molecular heterogeneity, and lack of actionable targets. This study identifies activation-induced cytidine deaminase (AID) as a pivotal epigenetic driver reprogramming the tumor microenvironment (TME) via non-canonical regulation of NOTCH signaling. Mechanistically, AID recruits histone acetyltransferase 1 (HAT1) to form a chromatin-remodeling complex that binds the JAG1 promoter region (-1.5 kb to -1.1 kb), inducing H4K5 acetylation and transcriptional activation. This AID/HAT1-JAG1 axis amplifies NOTCH signaling in TNBC models, and genetic ablation of either AID or JAG1 suppresses malignant progression. Pharmacological disruption using 4-Deoxyuricine (AID antagonist) and MG149 (HAT1 inhibitor) reduces JAG1 acetylation, attenuates NOTCH signaling, and reshapes the TME by depleting AID/HAT1-JAG1 axis and enhancing the infiltration of T cells, NK cells, and B cells. Clinically, AID and JAG1 co-expression enhances immune cell infiltration in TME, which predicts poor survival in TNBC cohorts. Our findings redefine AID's role beyond its function in mediating mutagenesis, positioning it as a master epigenetic regulator of TNBC plasticity through acetylation-dependent NOTCH activation. These results resolve the paradox of NOTCH inhibitor resistance by identifying JAG1's epigenetic priming as a prerequisite for ligand-receptor signaling. Targeting the AID/HAT1-JAG1 axis offers a dual therapeutic strategy to overcome TME-mediated therapy resistance and provides a blueprint for precision immunotherapy in AID-positive TNBC subgroups.

2025-11-01·NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY

Nanomaterials for delivery of drugs and genes to disrupt notch signaling pathway in breast cancer

Review

作者: Km, Muhasina ; Nori, Lakshmi Prasanthi ; Pindiprolu, Sai Kiran S S ; Ahmad, Zubair ; Gummadi, Ramakrishna ; Dasari, Nagasen

Breast cancer, marked by considerable heterogeneity and intricate molecular subgroups, poses substantial obstacles to therapy. Epithelial-mesenchymal transition (EMT) and the existence of tumor-initiating cells (TICs) facilitate treatment resistance, metastasis, and worse prognosis. The Notch signaling system has garnered significant interest for its involvement in promoting epithelial-mesenchymal transition (EMT), maintaining tumor-initiating cells (TIC), and facilitating cancer progression, especially in truculent subtypes such as triple-negative breast cancer (TNBC). Targeting the Notch system represents a promising therapeutic strategy; nevertheless, traditional inhibitors frequently encounter obstacles, including inadequate selectivity and bioavailability. Nanocarrier-based drug delivery systems provide novel therapeutic strategies to these difficulties by augmenting the targeted delivery of Notch inhibitors and enhancing therapeutic efficacy. Solid lipid nanoparticles (SLNs), polymeric nanoparticles, lipid-based nanocarriers, and micelles exhibit promise in delivering Notch inhibitors to neoplastic cells, altering the Notch signaling pathway, and surmounting drug resistance. This review examines recent breakthroughs in nanocarrier systems aimed at the Notch signaling pathway in breast cancer, highlighting the therapeutic potential of integrating nanomedicine with Notch inhibition to disrupt epithelial-mesenchymal transition (EMT), tumor-initiating cells (TICs), and metastasis, thereby enhancing clinical outcomes.

2025-10-11·[Zhonghua yan ke za zhi] Chinese journal of ophthalmology

[Advances in the molecular pathogenesis of lacrimal gland adenoid cystic carcinoma and associated targeted therapies].

Review

作者: Jiang, L B ; Li, B ; Jia, Y R

Lacrimal gland adenoid cystic carcinoma (LGACC), the most prevalent malignant epithelial tumor of the lacrimal gland, exhibits high invasiveness and poor prognosis. Despite aggressive local therapies, the 5-year and 10-year survival rates remain at 50% and 20% respectively. This review comprehensively synthesizes histopathological features, molecular mechanisms, and therapeutic advances in LGACC. Histopathological analysis highlights three classical subtypes (tubular, cribriform, and solid) with distinct prognostic implications, particularly emphasizing the detrimental survival impact of tumors undergoing high-grade transformation. At the molecular level, in-depth elucidation reveals the pivotal roles of NOTCH pathway mutations and MYB overexpression in driving oncogenesis through hyperactivation of receptor tyrosine kinase, PIP3/AKT, and ATR/BRCA signaling cascades. Current evidence demonstrates persistent therapeutic challenges: expanded surgical resection fails to significantly improve survival outcomes, while local excision combined with adjuvant therapies still faces substantial recurrence (80% at 5 years) and metastasis rates (66.9%). Emerging breakthroughs in targeted therapies warrant attention, including antisense oligonucleotides targeting MYB-NFIB fusion genes, clinical trial data of NOTCH inhibitors (e.g., AL101), and PARP inhibitor-based combinatorial regimens leveraging DNA damage repair mechanisms. By integrating fundamental research and clinical translational evidence, this review provides a theoretical framework for optimizing LGACC diagnosis and treatment paradigms.

100 项与 Notch inhibitors(Maastricht University) 相关的药物交易

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