bims-merabr 2026-01-11 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2026–01–11
eight papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

FOXM1/FUS facilitates triple-negative breast cancer malignant progression and glutamine metabolism through mediating SLC7A5 transcription.
Targeting the NAT10-HDAC4 positive feedback loop counteracts immunosuppression in breast cancer.
Crosstalk between TGF-β and Wnt/β-catenin signaling drives fibrogenic and stem-like phenotypes in senescent MDA-MB-231 breast cancer cells.
Astrocytes Protect Brain Metastatic Breast Cancer Cells From Chemotherapy Through CX43 Dependent STAT1 Signaling in Co-Culture Spheroids.
Exploring the Role of APC in Modulating Chemotherapeutic Response in Triple-Negative Breast Cancer cells.
Tumor-associated neutrophils drive liver-specific metastatic progression in breast cancer through methionine metabolism mediated by methionine adenosyltransferase II alpha.
Targeting the IGF1/Twist1 axis: A novel mechanism for β-elemene-induced anoikis and EMT inhibition in breast cancer cells.
MAZ-Mediated ubiquitin-conjugating enzyme E2C upregulation promotes breast cancer progression via the MAPK signaling pathway.

J Mol Histol. 2026 Jan 06. 57(1): 23

FOXM1/FUS facilitates triple-negative breast cancer malignant progression and glutamine metabolism through mediating SLC7A5 transcription.

Shuangjian Li, Qian Zhao.

  Triple-negative breast cancer (TNBC) is highly malignant with rising incidence and mortality. Solute carrier family 7 member 5 (SLC7A5) is an amino acid transporter, and its mechanism in TNBC is still unclear. The public databases (TIMER2.0, TCGA, GEPIA, Kaplan-Meier Plotter, linkedomics, RBPmap, and RBPDB) were used to analyze the expression and correlation of genes and prognosis correlation. Gene and protein expression was detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot. 3-(4, 5)-Dimethylthiahiazo (-z-y1)-3, 5-di-phenytetrazoliumromide (MTT), terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) staining, flow cytometry, transwell, sphere/tube formation, and metabolic kits were used to assess cell viability, apoptosis, invasion, stemness, angiogenesis, and glutamine (Gln) metabolism. The binding of forkhead box M1 (FOXM1) to the SLC7A5 promoter was determined by dual-luciferase reporter assay/chromatin immunoprecipitation (ChIP). RNA binding protein immunoprecipitation (RIP), RNA pull-down, and actinomycin D (Act D) experiments evaluated fused in sarcoma (FUS)-SLC7A5 interaction. In vivo, the mouse xenografts were established to validate the effects of FOXM1/SLC7A5 axis. Hematoxylin-eosin (HE) and immunohistochemistry (IHC) assays were used for histological morphology analysis and the protein expression of Ki67 and SLC7A5. SLC7A5 was up-regulated in TNBC and correlated with poor prognosis. Its knockdown repressed TNBC cell viability, invasion, stemness, angiogenesis, and Gln metabolism (as evidenced by reduced Gln, α-ketoglutarate (α-KG), and adenosine 5'-triphosphate (ATP) levles). FOXM1 transcriptionally activated SLC7A5; SLC7A5 overexpression reversed the suppressive effects of FOXM1 knockdown on TNBC malignancy and metabolism. Additionally, FUS bound to and stabilized SLC7A5 mRNA. In vivo, SLC7A5 counteracted the FOXM1 knockdown-mediated inhibition of tumor growth and the reduction in SLC7A5 and Ki67 protein expression. In conclusion, SLC7A5 promotes TNBC malignancy and metabolism. Its expression is transcriptionally driven by FOXM1 and post-transcriptionally stabilized by FUS. Targeting the FOXM1/SLC7A5 axis presents a novel therapeutic strategy for TNBC.

Keywords:  Forkhead box M1; Fused in sarcoma; Solute carrier family 7 member 5; Triple-negative breast cancer

DOI:  https://doi.org/10.1007/s10735-025-10674-2
J Exp Clin Cancer Res. 2026 Jan 07.

Targeting the NAT10-HDAC4 positive feedback loop counteracts immunosuppression in breast cancer.

Xin Ma, Shengye Jin, Xingda Zhang, Liuying Zhao, Haoran Wang, Siyu Liu, Hui Li, Qin Wang, Song Gao, Jianyu Wang, Yajie Gong, Yijun Chu, Crystal Song Zhang, Xi Chen, Da Pang, Cheng Qian, Hao Wu.

   BACKGROUND: N-acetyltransferase 10 (NAT10) mediated N4-acetylcytidine (ac4C) modification has been implicated in tumor progression; however, the precise role and underlying mechanism of NAT10 in breast cancer progression remain largely undefined.
METHODS: The expression and prognostic significance of NAT10 in breast cancer were evaluated using clinical tissue samples and public databases. Functional assays were performed in vitro and in vivo to assess the effects of NAT10 on tumor growth and immune evasion. Mechanistic studies, including RNA immunoprecipitation (RIP), ac4C RNA immunoprecipitation (acRIP), and co-immunoprecipitation (Co-IP), were conducted to elucidate the interaction between NAT10 and histone deacetylase 4 (HDAC4) and their roles in regulating NF-κB signaling and programmed death-ligand 1 (PD-L1) expression.
RESULTS: NAT10 expression was significantly upregulated in breast cancer and correlated with poor patient prognosis. NAT10 mediated ac4C modification enhanced the stability of HDAC4 mRNA, thereby promoting HDAC4 expression. Conversely, HDAC4 stabilized NAT10 protein through post-transcriptional deacetylation, forming a self-reinforcing regulatory loop. Elevated HDAC4 activated the NF-κB signaling pathway, resulting in increased PD-L1 transcription and enhanced immune evasion of breast cancer cells. Inhibition of the NAT10/HDAC4/NF-κB axis markedly reduced PD-L1 expression and restored antitumor immune responses.
CONCLUSION: Our findings identify a self-reinforcing NAT10/HDAC4 signaling circuit that drives breast cancer progression and immune evasion. Targeting NAT10 represents a promising therapeutic strategy to overcome immunosuppression and improve patient outcomes in breast cancer.

Keywords:  HDAC4; Immunosuppression; NAT10; PD-L1; ac4C modification

DOI:  https://doi.org/10.1186/s13046-025-03638-7
NPJ Aging. 2026 Jan 03.

Crosstalk between TGF-β and Wnt/β-catenin signaling drives fibrogenic and stem-like phenotypes in senescent MDA-MB-231 breast cancer cells.

Mona El Samarji, Elissa Alam, Mariam Dakramanji, Mariam Bassam, Jana Santina, Marc Ayoub, Alex Aprahamian, Mohamad Rima.

Genotoxic drugs used to treat cancer can trigger senescence, which contributes to chemotherapy resistance and tumor heterogeneity. However, the resulting cellular and molecular alterations following senescence remain poorly characterized. In this study, chemotherapy-induced senescence was triggered by etoposide in MDA-MB-231 breast cancer cells, and their fibrogenic potential, epithelial-to-mesenchymal transition (EMT), and stemness features were examined. In these cells, key mediators of fibrosis were significantly upregulated, suggesting a profibrotic potential involving TGF-β signaling. Etoposide also accentuated the mesenchymal phenotype of MDA-MB-231 cells and increased their motility. Additionally, nuclear β-catenin accumulation and upregulation of its EMT target genes were observed in senescent cells, alongside increased stemness markers, indicating a plastic cellular state involving Wnt/β-catenin signaling. Interestingly, pharmacological inhibition of the TGF-β/Wnt/β-catenin pathways reduced fibrosis, EMT, stemness marker expression, and cell migration, suggesting that these pathways are key regulators of these processes in senescent cells. These findings provide new insights into the molecular mechanisms driving chemotherapy-induced senescence and highlight these pathways as potential targets to alleviate resistance and aggressiveness in breast cancer.

DOI: https://doi.org/10.1038/s41514-025-00322-0
Biotechnol Bioeng. 2026 Jan 04.

Astrocytes Protect Brain Metastatic Breast Cancer Cells From Chemotherapy Through CX43 Dependent STAT1 Signaling in Co-Culture Spheroids.

Venu Yakati, Shreyas S Rao.

  Annually, over 200,000 cancer patients in the United States are diagnosed with brain metastases. Notably, brain metastatic breast cancer (BMBC) is the second most common, accounting for ~30% of all brain metastasis cases. BMBC typically has poor prognosis and is resistant to chemotherapy. In the brain tumor environment, metastatic cells interact with stromal cells, such as astrocytes, influencing tumor growth and protecting them from chemotherapy. Herein, we report a three-dimensional (3D) co-culture spheroid model to study astrocyte induced growth and chemoresistance in BMBC cells. We prepared co-culture spheroids of BMBC cells and human astrocytes (1:1 ratio) or only BMBC cell spheroids, cultured them in suspension for 7 days, and treated them with paclitaxel (PTX). Using proliferation and apoptosis assays our results demonstrate that tumor cells in co-culture spheroids were non-responsive to PTX, while the tumor cell spheroids were responsive. Moreover, the chemoprotection of tumor cells by astrocytes in co-culture spheroids was mediated by connexin 43 (CX43) dependent STAT1 signaling pathway. Accordingly, the inhibition of CX43 alleviated PTX resistance in co-culture spheroids. Our 3D co-culture spheroid platform could serve as a tool to study resistance to therapy in BMBC, and to identify combination treatments for therapy resistant BMBC.

Keywords:  CX43 signaling; brain metastasis; breast cancer; chemoresistance; co‐culture; spheroids

DOI:  https://doi.org/10.1002/bit.70144
bioRxiv. 2026 Jan 02. pii: 2025.12.31.697243. [Epub ahead of print]

Exploring the Role of APC in Modulating Chemotherapeutic Response in Triple-Negative Breast Cancer cells.

T Murlidharan Nair, Monica K VanKlompenberg, Jenifer R Prosperi.

Triple-negative breast cancer (TNBC) lacks targeted therapies and often develops chemoresistance. Since loss of the tumor suppressor APC is common in TNBC, we investigated how APC depletion alters transcriptional adaptation to chemotherapy using RNA-seq profiling of MDA-MB-157 cells and APC knockdown derivatives under control, cisplatin, and paclitaxel treatment. Pathway analyses of the transcriptomes showed that APC knockdown induces extensive remodeling of DNA-damage response, mitochondrial metabolism, inflammatory signaling, and chromatin accessibility, establishing stress-adapted transcriptional states aligned with paclitaxel tolerance (APC_shRNA1) or cisplatin resilience (APC_shRNA2). Machine-learning feature selection (Random Forest + PLS-DA) identified a 43-gene discriminant signature enriched for regulators of cell cycle and DNA repair (CCNB3, ORC1, E2F2, UNG), cytokine signaling (CXCL2, IL11), and metabolic support. These findings suggest that APC loss primes TNBC cells for chemotherapy persistence through an energetically reinforced, transcriptionally flexible survival program, highlighting DDR-OXPHOS-translation and inflammatory circuits as potential therapeutic vulnerabilities.

DOI: https://doi.org/10.64898/2025.12.31.697243
Transl Cancer Res. 2025 Dec 31. 14(12): 8949-8964

Tumor-associated neutrophils drive liver-specific metastatic progression in breast cancer through methionine metabolism mediated by methionine adenosyltransferase II alpha.

Lifeng Huang, Shuang Zhen, Qi Wang, Yue Sun, Tian Ji, Rui Chen, Jue Wang, Qiannan Zhu, Dongwei Xu, Xiaoming Zha.

   Background: The mechanisms underlying the pronounced organotropism of breast cancer (BC) for the liver remain incompletely elucidated. This study aims to investigate the role of the tumor microenvironment (TME), particularly tumor-associated neutrophils (TANs), and their metabolic regulation in breast cancer liver metastasis (BCLM).
Methods: We employed a multi-level integrative approach. Bioinformatic analysis of Gene Expression Omnibus (GEO) datasets characterized the immune landscape of BCLM. Clinical specimens, and in vitro assays were utilized to define the functional interplay between TANs and BC cells. Metabolomic profiling of patient samples was conducted to characterize metabolic alterations in BCLM.
Results: A neutrophil-enriched TME was identified as a distinct feature of BCLM. Functional studies demonstrated that TANs enhance cancer stemness and chemoresistance by upregulating methionine adenosyltransferase II alpha (MAT2A), a key enzyme that activates methionine metabolism. What is more, pharmacological inhibition of MAT2A successfully reversed the pro-tumorigenic phenotypes induced by TANs. Metabolomic analysis of patient specimens provided direct clinical evidence for the specific activation of the methionine cycle in BCLM tissues.
Conclusions: Our work uncovers a neutrophil-driven, MAT2A-dependent activation of methionine metabolism as a critical metabolic mechanism fueling liver metastasis in BC. These findings position the TAN-MAT2A-methionine axis as a promising therapeutic target for the treatment of BCLM.

Keywords:  Breast cancer (BC); cancer stemness; liver metastasis; methionine metabolism; tumor-associated neutrophils (TANs)

DOI:  https://doi.org/10.21037/tcr-2025-aw-2278
Biochim Biophys Acta Gen Subj. 2026 Jan 03. pii: S0304-4165(26)00001-2. [Epub ahead of print] 130901

Targeting the IGF1/Twist1 axis: A novel mechanism for β-elemene-induced anoikis and EMT inhibition in breast cancer cells.

Haibin Yan, Xinyuan Wang, Yifei Mo, Yinan Huang, Zheng Fu, Lufan Xie.

   BACKGROUND: Anoikis resistance and epithelial-mesenchymal transformation (EMT) promote breast cancer spread. There is a positive correlation between twist family BHLH transcription factor 1 (Twist1) and anoikis resistance. Given the demonstrated therapeutic effect of β-elemene treatment on breast cancer, its effects on Twist1 and anoikis became the focus of our research.
METHODS: Breast cancer cells, MDA-MB-157 and MDA-MB-231, were treated with 25 and 50 μM concentrations of β-elemene. Breast cancer cell lines with insulin-like growth factor 1 (IGF1) overexpression and Twist1 knockdown were successfully constructed to further explore the relevant mechanisms. Cell viability and apoptosis were detected by cell counting kit 8 (CCK8) method and fluorescent staining, respectively. Scratch assay for the detection of cell migration ability. The expression levels of matrix metalloproteinase (MMP) 9, MMP2, vimentin, N-cadherin, E-cadherin, Twist1, IGF1 and other related proteins were measured by western blot.
RESULTS: β-elemene reduced cell viability and produced anoikis in a concentration-dependent manner. β-elemene decreased the expressions of MMP9 and MMP2, inhibited vimentin, N-cadherin, Twist1, IGF1 expressions and cell migration ability, and up-regulated E-cadherin. The overexpression of IGF1 reversed the regulatory effects of β-elemene on cell survival, anoikis, cell migration and associated protein expressions, but the knockdown of Twist1 can counteract the impact of IGF1 overexpression.
CONCLUSION: β-elemene modulates anoikis and EMT in breast cancer cells via the IGF1/Twist1 signaling pathway, offering novel insights for breast cancer therapy.

Keywords:  Anoikis; Breast cancer; Epithelial-mesenchymal transformation; Insulin-like growth factor 1/twist family BHLH transcription factor 1; Β-Elemene

DOI:  https://doi.org/10.1016/j.bbagen.2026.130901
Transl Oncol. 2026 Jan 06. pii: S1936-5233(25)00377-8. [Epub ahead of print]64 102646

MAZ-Mediated ubiquitin-conjugating enzyme E2C upregulation promotes breast cancer progression via the MAPK signaling pathway.

Jinhui Bai, Mei Deng, Xueting Wu, Chao Xiong, Huixian Wu, Li Wang, Jie Qin.

   BACKGROUND: Malignant proliferation and invasion of tumor cells are the primary causes of death among patients with breast cancer, yet the molecular mechanisms orchestrating cancer metastasis are not well elucidated. Ubiquitin-conjugating enzyme E2C (UBE2C) has been reported to be involved in the tumorigenesis and development of various malignant tumors; however, the biological roles and underlying mechanisms of UBE2C in breast cancer remain unclear.
METHODS: UBE2C expression was analyzed in breast cancer tissue and cell lines using immunohistochemistry, quantitative reverse transcription PCR (RT-qPCR) and Western blot. The biological roles of UBE2C and its transcription factor MAZ were investigated in vitro using CCK-8, plate cloning, scratch, Transwell, cell cycle and apoptosis assays, while a nude mouse subcutaneous tumorigenic model was employed for the in vivo studies. Dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were conducted to validate the binding relationship between MAZ and UBE2C.
RESULTS: UBE2C expression is elevated in breast cancer, and higher levels of UBE2C are associated with poorer survival among patients with breast cancer. UBE2C promotes the progression of breast cancer both in vivo and in vitro. Additionally, UBE2C is a direct transcriptional target of MAZ, which also accelerates malignant development of breast cancer. Furthermore, UBE2C exerts its oncogenic effects dependent on the MAPK signaling pathway.
CONCLUSION: Our findings highlight the critical role of the MAZ/UBE2C/MAPK signaling axis in the progression of breast cancer and identify potential novel therapeutic targets for its treatment.

Keywords:  Breast cancer; MAPK; MAZ; Transcription factor; UBE2C

DOI:  https://doi.org/10.1016/j.tranon.2025.102646