Acetylation of Steroidogenic Acute Regulatory Protein Sensitizes 17β-Estradiol Regulation in Hormone-Sensitive Breast Cancer Cells DOI Open Access
Pulak R. Manna,

Deborah Molehin,

Ahsen U. Ahmed

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(16), P. 8732 - 8732

Published: Aug. 10, 2024

An imbalance in estrogen signaling is a critical event breast tumorigenesis. The majority of cancers (BCs) are hormone-sensitive; they majorly express the receptor (ER+) and activated by 17β-estradiol (E2). steroidogenic acute regulatory protein (StAR) mediates rate-limiting step steroid biosynthesis. dysregulation epigenetic machinery, modulating E2 levels, primary occurrence for promoting StAR expression, concomitant with synthesis, was reported to be aberrantly high human mouse hormone-dependent BC cells compared their non-cancerous counterparts. However, mechanism action remains poorly understood. We discovered as an acetylated have identified number lysine (K) residues that putatively malignant non-malignant cells, using LC-MS/MS (liquid chromatography–tandem mass spectrometry), suggesting differently influence synthesis mammary tissue. treatment hormone-sensitive MCF7 variety histone deacetylase inhibitors (HDACIs), at therapeutically clinically relevant doses, few additional residues. Among total fourteen acetylomes undergoing acetylation deacetylation, K111 K253 were frequently recognized either endogenously or response HDACIs. Site-directed mutagenesis studies these two acetylomes, pertaining K111Q K253Q mimetic states, resulted increases levels ER+ triple negative MB-231 values seen StAR. Conversely, carrying K111R K253R deacetylation mutants diminished These findings provide novel mechanistic insights into intra-tumoral regulation elucidating functional importance this uncovered post-translational modification (PTM), involving events, underscoring potential therapeutic target BC.

Language: Английский

Understanding the tumor microenvironment for personalized immunotherapy in early-onset head and neck squamous cell carcinoma DOI Creative Commons

Yidan Shan,

Di He,

Feng-guo Yan

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 2, 2025

Early-onset head and neck squamous cell carcinoma (HNSCC) has been increasingly observed in recent years, exhibiting distinct tumor behavior a unique microenvironment (TME) compared to older age groups. Studies suggest that early-onset HNSCC is associated with specific risk factors prognostic outcomes, while the underlying mechanisms driving these age-related differences remain unclear. In this review, we systematically examined original studies involving young patient samples, focusing on characteristics of TME potential for personalized immunotherapy. While further evidence needed, our findings indicate often exhibits higher aggressiveness immune suppression. Consequently, tailored immunotherapy may offer promising therapeutic strategy population.

Language: Английский

Citations

0
ADAR1 Regulates Lipid Remodeling through MDM2 to Dictate Ferroptosis Sensitivity DOI Open Access
Che-Pei Kung,

Nick Terzich,

Ma Xenia G. Ilagen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 21, 2025

Triple-negative breast cancer (TNBC), lacking expression of estrogen, progesterone, and HER2 receptors, is aggressive lacks targeted treatment options. An RNA editing enzyme, adenosine deaminase acting on 1 (ADAR1), has been shown to play important roles in TNBC tumorigenesis. We posit that ADAR1 functions as a homeostatic factor protecting from internal external pressure, including metabolic stress. tested the hypothesis iron- dependent cell death pathway, ferroptosis, ADAR1-protected vulnerability by showing knockdown sensitizes cells GPX4 inhibitors. By performing single-reaction monitoring-based liquid chromatography coupled mass spectrometry (LC-MS) measure intracellular lipid contents, we showed loss increased abundance polyunsaturated fatty acid phospholipids (PUFA-PL), which peroxidation primary driver ferroptosis. Transcriptomic analyses led discovery proto-oncogene MDM2 contributing remodeling upon loss. A phenotypic drug screen using ferroptosis-focused library was performed identify FDA- approved cobimetinib drug-repurposing candidate synergize with suppress demonstrating regulates fitness through desensitizing aim leverage this inform basic, pre-clinical, clinical studies develop novel therapeutic strategies for TNBC.

Language: Английский

Citations

0
Dual‐Gating Strategy: Ultrasound Activation of TRPV2 Channels and Borate‐Glass‐Induced Calcium Overload for Tumor Suppression DOI Creative Commons

Hai-Hong Zhu,

Liping Ouyang, Yijie Huang

et al.

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 27, 2025

Abstract Effective and precise treatment of breast cancer, particularly with bone metastasis, remains a significant challenge. Here, dual‐gating strategy combining locally delivered borate glass (BG) ultrasound (US) is developed for the effective inhibition cancer by targeting transient receptor potential vanilloid 2 (TRPV2). The results demonstrate that after local delivery BG to solid tumor, US effectively triggers calcium overload activating overexpressed TRPV2 channels, leading mitochondrial autophagy apoptosis in cells, thereby inhibiting tumor growth high precision. These effects are validated subcutaneous, orthotopic, TRPV2‐overexpressing mouse models. In metastasis model, combined simultaneously suppresses promotes regeneration. Overall, this offers safe efficient approach cancers expression provides new insights into design clinical translation calcium‐overload‐based therapies.

Language: Английский

Citations

0
α-Hederin causes ferroptosis in triple-negative breast cancer through modulating IRF1 to suppress GPX4 DOI
Xue Wu,

Lingli Jin,

Disuo Ren

et al.

Phytomedicine, Journal Year: 2025, Volume and Issue: 141, P. 156611 - 156611

Published: March 8, 2025

Language: Английский

Citations

0
Cellular Epigenetic Targets and Epidrugs in Breast Cancer Therapy: Mechanisms, Challenges, and Future Perspectives DOI Creative Commons

Ibrahim S. Alalhareth,

Saleh M. Alyami,

Abdulrhman Alshareef

et al.

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(2), P. 207 - 207

Published: Feb. 3, 2025

Breast cancer is the most common malignancy affecting women, manifesting as a heterogeneous disease with diverse molecular characteristics and clinical presentations. Recent studies have elucidated role of epigenetic modifications in pathogenesis breast cancer, including drug resistance efflux characteristics, offering potential new diagnostic prognostic markers, treatment efficacy predictors, therapeutic agents. Key include DNA cytosine methylation covalent modification histone proteins. Unlike genetic mutations, reprogramming landscape epigenome promising targeted therapy for reversal resistance. Epidrugs, which target modifications, can provide novel options by reversing acquired to treatment. Currently, approach involves combination therapies consisting epidrugs immune checkpoint inhibitors. This review examines aberrant regulation initiation progression, focusing on related estrogen signaling, resistance, epithelial–mesenchymal transition (EMT). It existing drugs treating agents that modify DNA, inhibitors acetyltransferases, deacetylases, methyltransferases, demethyltransferases. also delves into ongoing combining other addresses upcoming obstacles this field.

Language: Английский

Citations

0
A Multimodal Framework to Uncover Drug-Responsive Subpopulations in Triple-Negative Breast Cancer DOI Open Access
Yue Wang, Santiago Haase, Austin A. Whitman

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

Abstract Understanding how individual cancer cells adapt to drug treatment is a fundamental challenge limiting precision medicine therapy strategies. While single-cell technologies have advanced our understanding of cellular heterogeneity, efforts connect the behavior broader tumor responses and uncover global trends across diverse systems remain limited. There growing availability bulk omics data, but lack centralized tools repositories makes it difficult study response globally, especially at level adaptation. To address this, we present multimodal framework that integrates treated untreated transcriptomics data identify responsive cell populations in triple-negative breast (TNBC). Our leverages population-scale from TNBC samples define seven main “identities”, each representing unique combinations biologically relevant genes. These identities are dynamic trackable, allowing us map them onto single patterns respond treatment. Unlike static classifications, this approach captures evolving nature states, revealing select few dominate drive population-level during Crucially, ability decode these through inherent noise provides clearer picture heterogeneous therapy. By identifying dominant their dynamics, can better predict entire tumors This insight essential for designing precise combination therapies tailored heterogeneity patient tumors, addressing variations ultimately determine therapeutic outcomes.

Language: Английский

Citations

0
Single-cell and transcriptome analyses revealed CTHRC1 a potential therapeutic target mediating invasion and tumor microenvironment in TNBC: experimental validation DOI Creative Commons
Hong Wan,

Zichen Ling,

Yuwei Xie

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: March 11, 2025

Background Investigating the pivotal role of CTHRC1 in tumor microenvironment triple-negative breast cancer (TNBC). Method The RNA transcriptomic data obtained from Cancer Genome Atlas and single-cell sequencing TNBC Gene Expression Omnibus (GEO) were acquired subjected to analysis. A comprehensive investigation was conducted with a specific focus on characterizing its correlation invasive genes. Furthermore, additional analyses performed explore relationship between CTHRC1, immune cell infiltration, immunotherapy TNBC. expression microenvironment, cellular differentiation, communication systematically analyzed using Result patients gradually increases concomitantly progression T-stage N-stage. Simultaneously, there is concurrent increase most gene sets. significant augmentation both infiltration abundance activity M2-type macrophages associated elevated levels expression. Single-cell reveal an upregulated set CTHRC1-positive fibroblasts (CAFs), thereby modulating their interaction macrophages. Multiple immunofluorescence confirmed that modulates invasion through mediation CAFs. Conclusion molecule exhibits characteristic positive CAFs exert regulatory effects within immunosuppressive by

Language: Английский

Citations

0
Why combine and why neoadjuvant? Tumor immunological perspectives on chemoimmunotherapy in triple-negative breast cancer DOI Creative Commons
Kazuhiro Kakimi, Tomoharu Sugie

Breast Cancer, Journal Year: 2025, Volume and Issue: unknown

Published: May 6, 2025

Language: Английский

Citations

0
Bio-Pathological Functions of Posttranslational Modifications of Histological Biomarkers in Breast Cancer DOI Creative Commons

Anca-Narcisa Neagu,

Claudiu-Laurentiu Josan,

Taniya Jayaweera

et al.

Molecules, Journal Year: 2024, Volume and Issue: 29(17), P. 4156 - 4156

Published: Sept. 2, 2024

Proteins are the most common types of biomarkers used in breast cancer (BC) theranostics and management. By definition, a biomarker must be relevant, objective, stable, quantifiable biomolecule or other parameter, but proteins known to exhibit variate profound structural functional variation. Thus, proteome is highly dynamic permanently reshaped readapted, according changing microenvironments, maintain local cell tissue homeostasis. It that protein posttranslational modifications (PTMs) can affect all aspects function. In this review, we focused our analysis on different PTMs histological BC. analyzed PTMs, including phosphorylation, acetylation, methylation, ubiquitination, SUMOylation, neddylation, palmitoylation, myristoylation, glycosylation/sialylation/fucosylation transcription factors, proliferation marker Ki-67, plasma membrane proteins, histone modifications. Most these occur presence cellular stress. We emphasized interfere with maintenance, turnover lifespan, nuclear subcellular localization, structure function, stabilization inactivation, initiation silencing genomic non-genomic pathways, transcriptional activities signaling mitosis, proteostasis, cell–cell cell–extracellular matrix (ECM) interactions, trafficking, PPIs. Moreover, orchestrate hallmark pathways dysregulated BC, playing both pro- and/or antitumoral context-specific roles DNA damage, repair stability, inactivation/activation tumor-suppressor genes oncogenes, phenotypic plasticity, epigenetic regulation gene expression non-mutational reprogramming, proliferative signaling, endocytosis, death, TME, invasion metastasis, epithelial–mesenchymal/mesenchymal–epithelial transition (EMT/MET), resistance therapy reversal multidrug resistance. nucleus also at cytoplasmic level induce translocation opposite effects. Analysis allows for discovery validation new mainly early diagnosis, like extracellular vesicle glycosylation, which may considered as potential source circulating biomarkers.

Language: Английский

Citations

2
Nanoparticle‐Based drug delivery strategies for targeted therapy to hypoxic solid tumors DOI

ZhouXue Wu,

Junru Chen,

Biqiong Wang

et al.

Chemical Engineering Journal, Journal Year: 2024, Volume and Issue: unknown, P. 158081 - 158081

Published: Nov. 1, 2024

Language: Английский

Citations

2