bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2025–11–23
seven papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. EBF3 transcriptionally activates ACADL to block the Hippo/YAP signaling pathway and inhibits breast cancer progression.
  2. PGK1 Persulfidation Promotes the Proliferation and Metastasis of Breast Cancer.
  3. YTHDF3 promotes breast cancer osteolytic bone metastasis by enhancing the translation of ZEB1 and SMAD5.
  4. Epithelial-mesenchymal transition and tumor-associated macrophage axis in metastatic breast cancer: converging mechanisms and therapeutic perspectives.
  5. Anti-tumor response by targeting glucose metabolism and depletion of membrane cholesterol in breast cancer and melanoma cells.
  6. Exosomal transfer of miR-124 from engineered NK-92 cells inhibits breast cancer cell migration and induces apoptosis.
  7. Exploring the biological mechanisms of obesity affecting breast cancer from a multidimensional perspective.
  1. Pathol Res Pract. 2025 Nov 17. pii: S0344-0338(25)00492-3. [Epub ahead of print]277 156299
    EBF3 transcriptionally activates ACADL to block the Hippo/YAP signaling pathway and inhibits breast cancer progression.
    Caihong Cao, Xing Feng.
       OBJECTIVE: Breast cancer (BC) is the chief cause of malignancy-related deaths in women. This paper investigates how the EBF3-ACADL axis inhibits BC progression through Hippo/YAP signaling.
    METHODS: The differentially expressed gene ACADL in BC was screened by the bioinformatics databases, and ACADL expression in BC tumors and cells was verified by immunohistochemistry, RT-qPCR, and western blot analysis. BC cells were infected with an overexpressing-ACADL lentivirus to examine the effect of ACADL on BC cell growth. The in vivo impact of ACADL was investigated by constructing a xenograft tumor model. Cells were treated with XMU-MP-1, an inhibitor of MST1/2 kinase, to study the influence of ACADL on BC progression through the Hippo/YAP pathway. The upstream mechanism of abnormally elevated ACADL expression was analyzed by bioinformatics, and EBF3 expression in BC tumors and cells was verified. Regulatory assays were performed to confirm the binding relationship between ACADL and EBF3.
    RESULTS: ACADL and EBF3 were poorly expressed in BC tissues and cell lines. ACADL overexpression blocked p-YAP (Ser127), nuclear YAP localization, and canonical target genes (CTGF, CYR61, and ANKRD1), thereby suppressing BC cell growth and xenograft tumor development. XMU-MP-1 reversed the suppressive effect of ACADL overexpression on BC progression. EBF3 transcriptionally activated ACADL expression by binding to its promoter. EBF3 overexpression suppressed the malignant behavior of BC cells and xenograft tumor development in mice, which was reversed by ACADL knockdown.
    CONCLUSION: EBF3 transcriptionally activates ACADL and blocks the Hippo/YAP pathway to inhibit BC progression.
    Keywords:  ACADL; Breast cancer; EBF3; Hippo/YAP signaling pathway; Transcriptional activation
    DOI:  https://doi.org/10.1016/j.prp.2025.156299
  2. Antioxid Redox Signal. 2025 Nov 12. 0
    PGK1 Persulfidation Promotes the Proliferation and Metastasis of Breast Cancer.
    Chenghua Luo, Mengmeng Zhao, Yalu Wang, Yuxiang Xu, Shuai Chen, Weihua Liang, Kaige Yang, Jianming Hu.
      Aims: Endogenous hydrogen sulfide (H2S) is involved in the occurrence and development of breast cancer, while its underlying mechanism is not yet clear. Here, we aimed to focus on the molecular mechanism of endogenous H2S promoting the proliferation and metastasis of breast cancer. Results: In this study, four major findings were revealed: (1) Inhibition of cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) increased the content of glucose in the supernatant of breast cancer cell and decreased the production of intracellular lactic acid and adenosine triphosphate. (2) Phosphoglycerate kinase 1 (PGK1) was persulfidated at Cys108 and Cys316, and its persulfidation level in breast cancer tissue was significantly higher than that in paracancerous tissue. (3) Blocking the persulfidation of PGK1 inhibited glycolysis and malignant biological behaviors of breast cancer cell. (4) The CSE inhibitor reduced the persulfidation of PGK1 and inhibited the growth and metastasis of xenograft tumors, whereas sodium hydrosulfide reversed the effect of CSE inhibitor. Preface PGK1 is not the only potential target for persulfidation. Innovation and Conclusion: This study revealed a novel mechanism involved in the upregulation of endogenous H2S in breast cancer. Endogenous H2S regulates glycolysis of breast cancer cells by mediating PGK1 persulfidation modification at Cys108 and Cys316, thereby promoting tumor proliferation and metastasis. This study offers a potential therapeutic strategy through targeting the upregulated endogenous H2S and persulfidation of PGK1. Antioxid. Redox Signal. 00, 000-000.
    Keywords:  PGK1; breast cancer; hydrogen sulfide; persulfidation
    DOI:  https://doi.org/10.1177/15230864251394334
  3. Oncogenesis. 2025 Nov 17. 14(1): 41
    YTHDF3 promotes breast cancer osteolytic bone metastasis by enhancing the translation of ZEB1 and SMAD5.
    Lun Xu, Qian Yu, Xu Peihang, Kun Li, Bingnan Wang, Yang Shao, Mo Cheng, Wending Huang, Qianlan Yao, Xu Feng, Shaoli Song, Shuoer Wang, Wangjun Yan.
      Bone metastsis in advanced breast cancer patients are usually osteolytic. A better understanding of the mechanisms in osteolytic metastasis is critical for the development of new therapies. YTH domain-containing family protein 3 (YTHDF3) has been reported to function as an N6-methyladenosine (m6A)-modified mRNA regulator. In this study, we found YTDHF3 expression was associated with clinical characteristics of breast cancer patients. YTHDF3 expression influenced the migration and invasion capacity of breast cancer cells in vitro and in vivo, and low expression of YTHDF3 suppressed cancer cell-induced osteoclast differentiation and osteolytic bone destruction. Moreover, we found YTHDF3 enhanced the translation of zinc finger E-box-binding protein 1 (ZEB1) and SMAD family member 5 (SMAD5) by reading the m6A modification sites in their mRNAs and further promoted the epithelial-mesenchymal transition (EMT) of breast cancer cells. Enhanced expression of ZEB1 promoted the transcription of bone morphogenetic protein inhibitors such as NOG, FST and CCN2, which boosts osteolytic metastasis. Furthermore, we newly found Wnt family member 5B (WNT5B) expression was regulated by ZEB1, also involved in osteolytic process. In conclusion, YTHDF3 plays an important role in osteolytic metastasis and it may serve as a potential prognostic biomarker and therapeutic target for breast cancer bone metastasis.
    DOI:  https://doi.org/10.1038/s41389-025-00583-0
  4. Life Sci. 2025 Nov 14. pii: S0024-3205(25)00720-9. [Epub ahead of print] 124084
    Epithelial-mesenchymal transition and tumor-associated macrophage axis in metastatic breast cancer: converging mechanisms and therapeutic perspectives.
    Christina E Wheeler, Samy Lamouille.
      Breast cancer is a leading cause of cancer-related death in women worldwide, mainly attributable to metastatic progression accounting for about 90 % of these fatalities. The metastatic cascade can be initiated by epithelial-mesenchymal transition (EMT), a molecular and cellular program in which cancer cells lose their cell-cell junctions and acquire a more invasive phenotype. EMT is induced by a range of signaling molecules and growth factors, contributing significantly to the metastatic capability of cancer cells. Within the tumor microenvironment, tumor-associated macrophages (TAMs) can promote EMT through secretion of such molecules including chemokines, Wnt, IL-6, and TGF-β. Additionally, tumor cells secrete chemokines that drive the differentiation of macrophages toward an anti-inflammatory, pro-tumorigenic phenotype. This alliance between breast cancer cells and TAMs increases tumorigenicity and facilitates metastasis, highlighting a critical field of study for the development of novel and more efficient treatments in breast cancer. In this review, we discuss the mechanisms of TAM and EMT interaction in breast cancer progression and metastasis, and potential therapeutic approaches to target this crosstalk.
    Keywords:  Breast cancer; Epithelial-mesenchymal transition; Metastasis; Signaling pathways; Therapeutics; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.lfs.2025.124084
  5. Biochim Biophys Acta Mol Cell Res. 2025 Nov 16. pii: S0167-4889(25)00193-4. [Epub ahead of print]1873(1): 120088
    Anti-tumor response by targeting glucose metabolism and depletion of membrane cholesterol in breast cancer and melanoma cells.
    Himanshi Yaduvanshi, Bhavana Deshmukh, Abhijeet Singh, Shyamananda Singh Mayengbam, Manoj Kumar Bhat.
      Enhanced lactate production and cholesterol accumulation in cancer cells are often correlated with poor prognosis and the development of resistance to therapies. This study investigates a unique dual-pronged approach for abrogating tumor development by combining methyl-β-cyclodextrin (MCD)-mediated cholesterol depletion with sodium oxamate (OXA)-induced inhibition of lactate dehydrogenase A. The cytotoxic effects of MCD and OXA were validated by MTT and long-term colony formation assay. Cell cycle arrest and apoptosis were assessed via flow cytometry. The involvement of key signaling intermediates in proliferative pathways was evaluated by immunoblotting. The Seahorse analyzer was used to measure the real-time metabolic flux in mouse cancer cells. In vivo, studies and immunophenotyping were performed to investigate the impact of MCD+OXA treatment on tumor growth and immune cell infiltration in tumor and periphery organs. The results indicate that concurrent administration of a low-dose MCD and OXA elicited a synergistic cytotoxic effect and retarded tumor progression while being non-toxic to vital organs. Mechanistically, this combination downregulated ERK/AKT signaling, induced apoptosis, and suppressed cellular metabolism at the glycolysis/OXPHOS level, including ATP production. Interestingly, it promoted the infiltration of effector Th1 cells and B cells, while reducing the presence of PMN-MDSCs in the tumor microenvironment and peripheral organs. These findings suggest that the combination of MCD and OXA provides a dual-targeted approach by disrupting cholesterol as well as lactate metabolism and eliciting an anti-tumor immune response, leading to a reduction in the growth of tumor cells. This pre-clinical strategy demonstrates potential advantages over single-agent treatment, which warrants further investigations for its therapeutic implications. SUMMARY BLURB: In pre-clinical investigations, co-targeting membrane cholesterol, and lactate dehydrogenase A with methyl-β-cyclodextrin and sodium oxamate inhibits cell growth and restricts breast cancer and melanoma tumor progression.
    Keywords:  Breast cancer; Cholesterol; Glucose metabolism; Lactate dehydrogenase; Melanoma
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.120088
  6. Med Oncol. 2025 Nov 18. 43(1): 6
    Exosomal transfer of miR-124 from engineered NK-92 cells inhibits breast cancer cell migration and induces apoptosis.
    Amirabbas Salmani, Amir Atashi, Mina Soufi Zomorrod, Mohammad Kamalabadi-Farahani, Asieh Heirani-Tabasi, Masoud Soleimani.
      This study aimed to investigate the feasibility of using engineered NK-92 cell-derived exosomes to deliver miR-124 to breast cancer cell lines and to assess the anti-tumor effects of these exosomes in breast cancer cell lines. In this study, the NK-92 cell line was genetically engineered to overexpress miR-124. Subsequently, exosomes were isolated from the modified cell line. The effects of these NK-92-miR-124 exosomes were assessed on the proliferation, apoptosis, and migration of three different subtypes of breast cancer cell lines (MCF-7, MDA-MB-231, and SK-BR-3) using MTT assays, Annexin V/PI staining, and scratch tests, respectively. Finally, the results from all experiments were compared with the outcomes obtained from the treatment of breast cancer cell lines with NK-92 exosomes. All comparisons were made under the same experimental conditions. Our findings demonstrated that miR-124 was effectively delivered to breast cancer cell lines via engineered NK-92-derived exosomes. Furthermore, these NK-92-miR-124-loaded exosomes exhibited notable anti-tumor effects, such as reducing cell proliferation and migration across all three breast cancer cell lines. Additionally, they significantly enhanced apoptosis in MCF-7 and MDA-MB-231 breast cancer cell lines compared to NK-92-derived exosomes. Our study demonstrated that engineered NK-92-derived exosomes can effectively deliver miR-124 to breast cancer cells, leading to reduced migration and enhanced apoptosis. However, the anti-tumor effects varied among different breast cancer cell lines.
    Keywords:  Breast cancer; Exosome; MiR-124; NK-92
    DOI:  https://doi.org/10.1007/s12032-025-03107-3
  7. Discov Oncol. 2025 Nov 21. 16(1): 2135
    Exploring the biological mechanisms of obesity affecting breast cancer from a multidimensional perspective.
    Yingying Rao, Suyuan Wang, Xianglin Liu, Changhua Shao, Hengyu Li.
      Obesity, a global health challenge, significantly contributes to breast cancer pathogenesis through chronic inflammation and metabolic dysregulation. This review summarizes the biological mechanisms through which obesity influences the development and progression of breast cancer, focusing on endocrine regulation, intercellular communication, gut microbiota interactions, obesity-associated genetic polymorphisms, and circadian rhythm homeostasis. The aim is to provide a theoretical foundation for the diagnosis and treatment of obesity-related breast cancer.
    Keywords:  BMI; Biological mechanisms; Breast cancer; Circadian homeostasis; High-fat diet; Intestinal microecology; Obesity; Tumor immune microenvironment
    DOI:  https://doi.org/10.1007/s12672-025-03838-9
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