bims-merabr 2025-09-07 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2025–09–07
nine papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

The Hypoxia-Induced Chromatin Reader ZMYND8 Drives HIF-Dependent Metabolic Rewiring in Breast Cancer.
Mechanistic study of the Tβ4/SLC7A11 signaling pathway regulating breast cancer evolution.
ATE1 promotes breast cancer progression via arginylation-dependent regulation of MAPK-MYC signaling.
Mammary Adipose Dysfunction in the Dual Epidemic of Obesity and Breast Cancer.
Hyperlipidemia drives tumor growth in a mouse model of obesity-accelerated breast cancer growth.
FOXO1- mediated argininosuccinate lyase transcription inhibits ammonia metabolism and breast cancer cell metastasis.
SOX9 Promotes Breast Cancer Progression via the EGFR/STAT3 Signaling Axis.
Unexplored gene PHKA1 interplays between glucose metabolism and breast cancer.
STAT3/Snail Signaling and Progression of Hypoxia Tolerance in Breast Cancer Cells.

J Biol Chem. 2025 Sep 03. pii: S0021-9258(25)02532-3. [Epub ahead of print] 110680

The Hypoxia-Induced Chromatin Reader ZMYND8 Drives HIF-Dependent Metabolic Rewiring in Breast Cancer.

Sandhik Nandi, Atanu Mondal, Ishita Sarkar, Md Wasim Akram Ddoza Hazari, Indrakshi Banerjee, Shantanu Ghosh, Himansu Roy, Abhra Banjerjee, Anjali Banyopadhyay, Shritama Aich, Sanghamitra Sengupta, Shilpak Chatterjee, Chandrima Das.

  Breast cancer, a leading cause of mortality, exhibits significant heterogeneity across molecular subtypes, with tumor hypoxia contributing to poor therapeutic outcomes. The present study investigates the role of ZMYND8, a hypoxia-responsive epigenetic factor, in regulating carbohydrate metabolism in concert with HIF1α in breast cancer. In adherent cells as well as in 3D MCTS, ZMYND8 expression is elevated under hypoxic conditions. Further Immunohistochemistry analysis also shows that ZMYND8 and HIF1α expression are positively correlated in breast cancer. Remarkably, ZMYND8 is found to regulate glycolysis in hypoxic breast cancer cells as well as in 4T1-induced breast tumors in mice, elevating the expression of Hexokinase II (HK II) and lactate dehydrogenase A (LDHA). Notably, ZMYND8 directly regulates the transcription of LDHA by promoting the recruitment of S5-phosphorylated RNA Polymerase II to its promoter region. Metabolic-flux analysis, along with Acetyl CoA and Lactate pool measurements confirm that ZMYND8 bifurcates the metabolic axis towards anaerobic glycolysis, leading to the increase of extracellular acidification in hypoxic conditions. Interestingly, ZMYND8-induced changes in metabolic intermediate lactate in breast cancer cells, as well as in mouse serum, significantly impact the immune cell invasion and CD8+ T cell activity in the tumor microenvironment. These results highlight ZMYND8 as a key player in hypoxia-induced metabolic reprogramming of breast cancer cells and provide new insights into the epigenetic regulation of cancer metabolism. Our study unveils a novel mechanism linking epigenetics, metabolism, and immune evasion in breast cancer, opening new avenues for targeted therapeutic interventions aimed at disrupting this axis.

Keywords:  Breast cancer; Chromatin; Gene expression; Glucose metabolism; Glycolysis; Hypoxia; Immune signalling; Lactate; Transcription

DOI:  https://doi.org/10.1016/j.jbc.2025.110680
Cell Signal. 2025 Sep 03. pii: S0898-6568(25)00526-1. [Epub ahead of print] 112111

Mechanistic study of the Tβ4/SLC7A11 signaling pathway regulating breast cancer evolution.

Zhaoyan Jin, Hongshu Li, Jiafeng Li, Ying Chang, Zhengri Piao, Quanxin Jin, Tiefeng Jin.

  Thymosin β4 (Tβ4) plays a critical role in breast cancer progression, yet its molecular mechanism remains unclear. In this study, we identified that Tβ4 is significantly upregulated in breast cancer tissues and cell lines, and its high expression correlates with poor clinical outcomes. Functionally, Tβ4 promotes breast cancer cell proliferation, migration, epithelial-mesenchymal transition (EMT), and angiogenesis while inhibiting apoptosis. Mechanistically, Tβ4 directly regulates the expression of SLC7A11, a key cystine/glutamate antiporter, thereby enhancing glutathione biosynthesis and suppressing lipid peroxidation to inhibit ferroptosis. Rescue experiments further demonstrated that silencing SLC7A11 abrogates the oncogenic effects of Tβ4 both in vitro and in vivo. Collectively, these findings uncover a novel Tβ4/SLC7A11 axis that modulates ferroptosis sensitivity and contributes to breast cancer malignancy, offering potential therapeutic implications for targeting ferroptosis resistance.

Keywords:  Breast cancer; Ferroptosis; SLC7A11; Thymosin beta-4 (Tβ4)

DOI:  https://doi.org/10.1016/j.cellsig.2025.112111
Cell Commun Signal. 2025 Sep 02. 23(1): 390

ATE1 promotes breast cancer progression via arginylation-dependent regulation of MAPK-MYC signaling.

Laxman Nawale, Shinyeong Ju, Jung Gi Kim, Nak Kyun Soung, Bo Yeon Kim, Cheolju Lee, Hyunjoo Cha-Molstad.

   BACKGROUND: Arginyl-tRNA-protein transferase (ATE1) catalyzes N-terminal arginylation, a regulatory protein modification implicated in various cellular processes, including proliferation, apoptosis, and migration. Although ATE1 has context-dependent roles in cancer, its specific function in breast cancer remains unclear. This study investigates the oncogenic role of ATE1 across multiple breast cancer subtypes and its underlying molecular mechanisms.
METHODS: ATE1 expression in breast cancer was evaluated using TCGA data and immunoblotting across breast cancer cell lines and normal mammary epithelial cells (HMEC). Functional studies using siRNA- and shRNA-mediated knockdown assessed ATE1's role in cell viability, clonogenic growth, migration, and tumorigenesis in vitro and xenograft models. Quantitative proteomics, R-catcher-based N-terminomics, and pathway analyses were employed to identify ATE1-dependent signaling networks, with a focus on MAPK-MYC axis regulation. Flow cytometry and immunoblotting were used to assess cell cycle progression, apoptosis, and MYC stability.
RESULTS: ATE1 was significantly upregulated in breast cancer cells and associated with poor prognosis in early-stage patients. ATE1 depletion selectively impaired viability, proliferation, and migration in breast cancer cells, but not in HMECs. In vivo, ATE1 silencing suppressed tumor growth in xenograft models. Proteomic profiling revealed that ATE1 regulates the cell cycle and survival pathways in a subtype-specific manner, particularly through modulation of the MAPK-MYC-CDK6 axis in luminal T-47D cells. ATE1 stabilized MYC protein via ERK-mediated phosphorylation at Ser62, promoting cell cycle progression and suppressing apoptosis. Rescue experiments confirmed that ATE1's tumor-promoting activity depends on its arginyltransferase function.
CONCLUSIONS: ATE1 promotes breast cancer progression by enhancing cell proliferation, survival, and migration through MAPK-dependent stabilization of MYC in a lineage-specific context. These findings identify ATE1 as a potential therapeutic target and highlight the relevance of protein arginylation in the molecular heterogeneity of breast cancer.

Keywords:  ATE1 (arginyltransferase 1); Breast cancer; Cell proliferation; Cell survival; MYC signaling; N-degron pathway; N-terminal arginylation; Tumor progression

DOI:  https://doi.org/10.1186/s12964-025-02376-9
Carcinogenesis. 2025 Sep 03. pii: bgaf053. [Epub ahead of print]

Mammary Adipose Dysfunction in the Dual Epidemic of Obesity and Breast Cancer.

Elvina Jeyakumar, Sathyavathi Sundararaju, Stephanie Annett, Mohamed A Elrayess.

  Breast cancer is one of the leading causes of death among women, with obesity being a significant factor. Mammary adipose tissue (MAT) dysfunction in obesity creates a tumor-supportive environment, leading to increased risk. In obesity, MAT undergoes significant changes, including increased adiposity, chronic inflammation, aromatase overexpression, insulin resistance, and altered adipokine signaling, collectively fostering a pro-tumorigenic microenvironment. The interaction between adipocytes and cancer cells further exacerbates breast cancer progression through metabolic crosstalk and immune evasion. This review examines the role of MAT dysfunction in breast cancer incidence and progression, in obesity. Interestingly, obesity appears have a paradoxical effect on breast cancer risk, offering a potentially protective role in premenopausal women, but increased risk in post-menopausal women, primarily due to differences in estrogen levels. Addressing the metabolic, inflammatory, and hormonal abnormalities in obese MAT can aid in enabling the development of precision therapies that reduce breast cancer risk and improve treatment outcomes in obese patients.

Keywords:  Adipokine imbalance; Breast cancer; Mammary adipose tissue; Menopause; Metabolic dysfunction; Obesity

DOI:  https://doi.org/10.1093/carcin/bgaf053
Cancer Metab. 2025 Aug 28. 13(1): 39

Hyperlipidemia drives tumor growth in a mouse model of obesity-accelerated breast cancer growth.

Renan Fl Vieira, Sawyer R Sanchez, Menusha Arumugam, Peyton D Mower, Meghan C Curtin, Abigail E Jackson, Molly R Gallop, Jillian Wright, Alexis Bowles, Gregory S Ducker, Keren I Hilgendorf, Amandine Chaix.

Obesity is an established risk factor for breast cancer (BC), yet the specific mechanisms driving this association remain unclear. Dysregulated lipid metabolism has emerged as a key factor in cancer cell biology, and, while obesity is often accompanied by hyperlipidemia, the isolated impact of elevated lipid levels on BC growth has not been experimentally tested. Using the E0771 and Py230 orthotopic models of obesity-accelerated BC growth in immune-competent mice, we investigated the role of systemic lipids on tumor growth. Combining dietary and genetic mouse models, we show that elevated circulating lipids are sufficient to accelerate BC tumor growth even in the absence of obesity or alterations in blood glucose and/or insulin levels. Pharmacological lowering of systemic lipid levels attenuates BC growth in obese mice, suggesting a direct role for lipids in fueling tumor expansion. Notably, we also show that weight loss alone, without a corresponding reduction in lipid levels such as that induced by a ketogenic diet, fails to protect against BC, highlighting the necessity of targeting lipid metabolism in obesity-associated BC. Our findings establish hyperlipidemia as a critical driver of BC progression and suggest that lipid-lowering interventions may be a promising strategy to mitigate BC risk in individuals with obesity.

DOI: https://doi.org/10.1186/s40170-025-00407-0
J Biol Chem. 2025 Sep 02. pii: S0021-9258(25)02529-3. [Epub ahead of print] 110677

FOXO1- mediated argininosuccinate lyase transcription inhibits ammonia metabolism and breast cancer cell metastasis.

Min Zhao, Dongdong Yuan, Mengmeng Wei, Jie Zhang, Wenjing Yang, Shaojie Qin, Le Li.

  Cancer cells exhibit altered and elevated metabolic processes to meet their increased bioenergetic and biosynthetic demands, leading to the production of ammonia as a byproduct. However, the mechanisms by which tumor cells manage excess ammonia remain poorly understood, despite its critical role in nitrogen metabolism. The urea cycle, a central pathway for ammonia detoxification, has been insufficiently explored in the context of cancer metabolism. In this study, we identify Forkhead box O1 (FOXO1), a transcription factor essential for tumorigenesis and progression, as a key regulator of the urea cycle in breast cancer cells. Specifically, FOXO1 inhibits argininosuccinate lyase (ASL) expression, a crucial enzyme in the urea cycle, leading to reduced ammonia detoxification. Mechanistic analyses reveal that ASL is a direct transcriptional target of FOXO1. Functionally, we demonstrate that FOXO1 modulates the migratory ability of breast cancer cells through the regulation of ASL and arginine metabolism. These findings unveil an unexpected role of FOXO1 in regulating the urea cycle in tumors and highlight a novel mechanism by which breast cancer cells exploit metabolic pathways to support their progression and metastasis. Our study provides valuable insights into cancer metabolism and identifies potential targets for therapeutic intervention.

Keywords:  ASL; Breast cancer metastasis; FOXO1; Urea cycle

DOI:  https://doi.org/10.1016/j.jbc.2025.110677
Curr Cancer Drug Targets. 2025 Aug 22.

SOX9 Promotes Breast Cancer Progression via the EGFR/STAT3 Signaling Axis.

Chunrui Zhang, Na Li, Fei Xue, Tipeng Zhang.

   INTRODUCTION: Sex-determining region Y-box 9 (SOX9) is a transcription factor frequently overexpressed in breast cancer, playing a critical role in tumor initiation, progression, and therapeutic resistance. While its oncogenic potential is recognized, the underlying molecular mechanisms remain incompletely elucidated. This study aimed to investigate the functional role of SOX9 in breast cancer, specifically focusing on its interaction with the EGFR/STAT3 signaling pathway.
METHODS: The study integrated bioinformatics analyses with functional assays in breast cancer cell lines to determine the effects of SOX9 modulation on cell proliferation, migration, and invasion, and to elucidate its connection with the EGFR/STAT3 signaling axis.
RESULTS: Our findings demonstrate that SOX9 promotes breast cancer cell proliferation, migration, and invasion. Mechanistically, this occurs through the activation of the EGFR/STAT3 signaling axis. Furthermore, targeting SOX9 effectively attenuated these oncogenic phenotypes in vitro.
DISCUSSION: The elucidation of SOX9's role in activating the EGFR/STAT3 pathway significantly advances our understanding of its oncogenic mechanisms in breast cancer. These findings are consistent with existing literature on SOX9's pro-tumorigenic impact and the established role of EGFR/STAT3 signaling in cancer progression, highlighting a crucial regulatory link. This newly identified SOX9-EGFR/STAT3 axis not only reinforces SOX9's prognostic value but also strongly supports its exploration as a novel therapeutic target.
CONCLUSION: These findings identify SOX9 as a key regulator of the EGFR/STAT3 signaling pathway in breast cancer. This highlights the potential of SOX9 as both a prognostic biomarker and a promising target for drug therapy in breast cancer.

Keywords:  Breast cancer; EGFR/STAT3 pathway; SOX9; cancer progression.; epidermal growth factor receptor; signal transducer and activator of transcription 3

DOI:  https://doi.org/10.2174/0115680096369386250717220332
Biochim Biophys Acta Mol Cell Res. 2025 Aug 27. pii: S0167-4889(25)00157-0. [Epub ahead of print]1872(8): 120052

Unexplored gene PHKA1 interplays between glucose metabolism and breast cancer.

Sweta H Makwana, Jyoti Poswal, Pooja Yadav, Shailendra P Singh, Chandi C Mandal.

  Cancer cells often undergo metabolic reprogramming, typically increasing their uptake and utilization of energy sources like glucose, fatty acids, lactate, glutamine, and pyruvate, while maintaining redox balance. Rather than relying on oxidative phosphorylation, cancer cells preferentially engage glycolysis to convert pyruvate into lactate. This metabolic reprogramming correlates with altered glucose metabolism and dysregulated insulin signalling. Diabetes is associated with increased risk of certain cancer types. Cancer database analysis of genes involved in glucose metabolism, insulin signalling and diabetes, identified an unexplored differentially expressed PHKA1 gene associated with poor patient survivability in breast cancer. Expression of the PHKA1 gene was found to be upregulated under an environment of high glucose and insulin in cancer cells. Silencing PHKA1 via siRNA led to marked decrease in proliferative, invasion, migratory, and stem-like properties of MDA-MB-231 and MCF-7 breast cancer cells. Experimental findings demonstrated reduced expression of mesenchymal markers (e.g., Vimentin, Zeb-1/2), cell cycle markers (e.g., CDK-2/4), and proliferative markers (e.g., Bcl-2 and Bcl-xl), while expression of epithelial markers (e.g., E-cadherin and Keratin-19) were enhanced in PHKA1 knockdown cells when compared to control. Performance of glycolysis stress and mito stress assay further demonstrated that siPHKA1 cells had diminished glycolytic activity alongside suppressed mitochondrial function. These findings highlight intricate relationship between metabolic dysregulation observed in diabetes, contributing to the progression of cancer. Collectively, these observations highlight PHKA1 as an oncogenic candidate with potential role in breast cancer. Comprehensive understanding of such metabolic alterations is critical to designing targeted therapeutic strategies aimed at mitigating breast cancer progression.

Keywords:  Breast cancer; Diabetes; Glucose metabolism; Glycolysis; Phosphorylase Kinase Regulatory Subunit Alpha 1 (PHKA1); siRNA-mediated knock-down

DOI:  https://doi.org/10.1016/j.bbamcr.2025.120052
Biochemistry (Mosc). 2025 Aug;90(8): 1064-1076

STAT3/Snail Signaling and Progression of Hypoxia Tolerance in Breast Cancer Cells.

Olga E Andreeva, Danila V Sorokin, Alexander M Scherbakov, Svetlana V Vinokurova, Pavel B Kopnin, Nadezhda V Elkina, Maria D Fedorova, Alexey N Katargin, Danila S Elkin, Mikhail A Krasil'nikov.

  One of the hallmarks of malignant neoplasms is their ability to sustain growth under hypoxic conditions resulting from insufficient oxygenation of tumor tissues. Prolonged hypoxia is associated with the gradual adaptation of tumor cells to low oxygen levels, leading to the enhanced survival, increased metastatic potential, and development of resistance to anticancer therapies. The aim of this study was to investigate the mechanisms underlying adaptation of breast cancer cell to prolonged hypoxia and maintenance of the hypoxia-tolerant phenotype. Using long-term culturing under low oxygen conditions (1% O2), we established hypoxia-adapted sublines of luminal (MCF-7) and triple-negative (MDA-MB-231) breast cancer cells, characterized by a stable growth in a hypoxic environment. The acquisition of hypoxia tolerance was accompanied by the activation of the HIF-1α-dependent transcription factor STAT3 and persistent overexpression of Snail, a key downstream effector of STAT3. The maintenance and stabilization of hypoxia-tolerant phenotype are mediated by miR-181a-2, which targets the STAT3/Snail signaling axis in the resistant cells. Analysis of DNA methylation status revealed no significant changes in the expression or activity of DNA methyltransferases (DNMTs) in the hypoxia-adapted cells. However, pharmacological inhibition of DNMTs using decitabine, as well as DNMT knockdown, increased cell sensitivity to hypoxia and partially reversed the hypoxia-resistant phenotype, which was accompanied by the activation of pro-apoptotic p53 signaling. In conclusion, our findings suggest that the acquired hypoxia tolerance in breast cancer cells is mediated, at least in part, by the activation of the miR-181a-2/STAT3/Snail signaling pathway. Furthermore, the use of demethylating agents may represent a promising therapeutic approach to targeting hypoxia-tolerant cancer cell populations.

Keywords:  STAT3; Snail; breast cancer; hypoxia; methylation; miR-181a-2

DOI:  https://doi.org/10.1134/S0006297925601315