bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2026–10–25
six papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. FABP4 Couples Lipid Metabolism to PD-L1 Stabilization in Immunosuppressive Myeloid Cells.
  2. CST1 Regulates ER-Mitochondrial Mg²⁺ Balance via MAGT1 to Promote Breast Cancer Metabolism and Growth.
  3. MYH9 confers doxorubicin resistance by stabilizing GRP78 and suppressing the PERK signaling-driven apoptotic pathway in breast cancer.
  4. Breast cancer cells with decreased fibronectin-integrin adhesion strength attenuate the malignancy of its microenvironment.
  5. Neutrophils alter the metabolic profile of a coculture model of triple-negative breast cancer and stromal cells.
  6. LINC01537 Regulates Malignant Phenotypes and Predicts Prognosis in Breast Cancer, and Its Bioinformatics Analysis.
  1. Cancer Immunol Res. 2026 Oct 21.
    FABP4 Couples Lipid Metabolism to PD-L1 Stabilization in Immunosuppressive Myeloid Cells.
    Jianyu Yu, Jonathan Shilyansky, Jiaqing Hao, Anthony Avellino, Yanwen Sun, Xingshan Jiang, Xiaochun Han, Melissa Curry, Sonia L Sugg, Bing Li.
      Metabolic dysregulation in obesity reshapes immune function, but how lipid signals drive immune suppression remains unclear. Herein, we identify a FABP4-PD-L1 axis that links lipid metabolism to immune checkpoint regulation in myeloid cells. Single-cell transcriptomics revealed a distinct FABP4high immunosuppressive splenic macrophage subset enriched under high-fat diet (HFD) conditions, characterized by impaired antigen presentation and elevated PD-L1 expression. Mechanistically, palmitic acid (PA) was shown to induce FABP4 and promote PD-L1 palmitoylation, leading to its stabilization on the cell surface independent of transcriptional regulation. FABP4 was essential for this process, which enabled PD-L1 surface stabilization, immunosuppression and mammary tumor progression. In humans, a conserved CD14intCD16⁺ monocyte population exhibited elevated FABP4-PD-L1 signaling and correlated with obesity and invasive breast cancer. These findings establish PD-L1 as a metabolically regulated protein and reveal a mechanism by which lipid excess drives immune evasion, suggesting FABP4 as a potential therapeutic target in cancer immunotherapy.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-26-0497
  2. Int J Biol Sci. 2026 ;22(15): 8230-8250
    CST1 Regulates ER-Mitochondrial Mg²⁺ Balance via MAGT1 to Promote Breast Cancer Metabolism and Growth.
    Wenqiang Gan, Min Zheng, Li Liu, Jingwen Liao, Yu Zhu, Xiaochen Hou, Qunshan Liu, Hui Li, Jing Yao, Dewei Jiang, Ceshi Chen.
      Breast cancer remains a clinical challenge and requires novel molecular targets. Here, we identify the Cystatin SN (CST1) as a critical oncoprotein upregulated in breast cancer, where its expression correlates with poor prognosis. Functionally, CST1 promotes breast cancer cell proliferation and tumor growth in vitro and in vivo, independent of its secretion. Mechanistically, CST1 physically interacts with the magnesium transporter MAGT1 on the endoplasmic reticulum (ER) membrane, and this interaction potentiates MAGT1-mediated Mg²⁺ transport, elevating mitochondrial Mg²⁺ levels and fueling mitochondrial metabolism. We developed a cell-penetrating peptide TAT-TM42 which disrupts the CST1-MAGT1 interface and effectively suppresses Mg²⁺ flux, mitochondrial metabolism, and tumor growth in vivo. Our study unveils a non-canonical role for a secreted protein in regulating inter-organelle ion homeostasis to drive cancer metabolism and growth, and proposes a targeted peptide-based strategy for treating breast cancer.
    Keywords:  CST1; MAGT1; breast cancer; magnesium; metabolism
    DOI:  https://doi.org/10.7150/ijbs.136015
  3. Front Oncol. 2026 ;16 1923603
    MYH9 confers doxorubicin resistance by stabilizing GRP78 and suppressing the PERK signaling-driven apoptotic pathway in breast cancer.
    Jing Jiang, Tianzi You, Ziyi Zhao, Binlei Sheng, Zhanqi Sun, Xujun Li.
       Background: MYH9 is upregulated in various malignancies, but its role in breast cancer chemoresistance remains unclear. We investigated whether MYH9 regulates doxorubicin (ADR) resistance via GRP78 stabilization and PERK pathway modulation.
    Methods: MYH9 expression was analyzed in breast cancer tissues and cell lines by immunohistochemistry and western blot. ADR-resistant MCF-7 and MDA-MB-231 cell lines were established. MYH9 knockdown/overexpression and GRP78 overexpression were achieved by lentiviral transduction. Protein interactions, degradation assays, PERK signaling, apoptosis, and in vivo drug responses were evaluated.
    Results: MYH9 was significantly upregulated in breast cancer tissues, particularly in triple-negative breast cancer (95.2%), and further elevated in ADR-resistant cells. MYH9 overexpression enhanced ADR tolerance, while knockdown sensitized resistant cells in vitro and in vivo. Mechanistically, MYH9 directly bound GRP78 (but not CALR or GRP94), inhibiting ubiquitin-mediated proteasomal degradation. MYH9 depletion reduced GRP78 levels and activated the PERK pathway (p-eIF2α, ATF4, CHOP), promoting apoptosis via Bax/Bad upregulation and Bcl-2 downregulation. ERS induction with thapsigargin enhanced ADR sensitivity, whereas 4-PBA attenuated it. GRP78 overexpression rescued ADR resistance, confirming GRP78 dependency.
    Conclusion: MYH9 confers ADR resistance in breast cancer by stabilizing GRP78 and suppressing PERK-driven apoptosis, identifying the MYH9/GRP78 axis as a potential therapeutic target for overcoming chemoresistance.
    Keywords:  ADR-resistant; GRP78; MYH9; breast cancer; endoplasmic reticulum stress
    DOI:  https://doi.org/10.3389/fonc.2026.1923603
  4. Matrix Biol. 2026 Oct 22. pii: S0945-053X(26)00109-5. [Epub ahead of print] 102067
    Breast cancer cells with decreased fibronectin-integrin adhesion strength attenuate the malignancy of its microenvironment.
    Natalia Burday, Gemma Guerrero-Barberà, Asier Jayo, Manuel M Sánchez Del Pino, Elena Ortiz-Zapater, Mercedes Costell.
      Fibronectin (FN), a key component of many solid tumors microenvironment, increases their mechanical stiffening and promotes cancer progression and metastasis. We studied Fn1syn/syn;PyMT mice carrying the breast cancer-inducing PyMT oncogene and a Fn1 gene with a nonfunctional synergy site (FNsyn), which impairs the reinforcement of the α5β1 integrin adhesion to the FN-RGD motif. Here, we show that Fn1syn/syn;PyMT mice exhibit delayed tumor onset in the mammary glands and reduced lung metastasis associated with decreased tumor vascularization, reduced cancer cell proliferation and lower abundance of ECM fibrillar proteins within the tumor stroma. Isolated cancer-associated fibroblasts with high αSMA expression levels (H-αSMA CAFs) and tumor cells reveal that FNsyn reduces their response when the substrate stiffness rises. Consequently, Fn1syn/syn CAFs express low αSMA and reduced Lysyl-2 and -3 oxidases leading to the assembly of loose fibrotic ECMs. Moreover, luminal breast cancer cells grown as organoids showed reduced incidence of invasive traits on stiff FNsyn substrates. Importantly, these key alterations were strongly correlated with the phenotypic changes observed in the stroma of Fn1syn/syn;PyMT tumors, contributing to the establishment of a microenvironment characterized by a reduced abundance of immunosuppressive cytokines and an increased infiltration of immune cells. Therapeutic targeting the FN synergy site is sufficient to reprogram the tumor microenvironment toward a less fibrotic and immunoactive state.
    Keywords:  a5b1 integrins; cancer microenvironment; fibronectin; fibrotic extracellular matrix; mechanosignaling
    DOI:  https://doi.org/10.1016/j.matbio.2026.102067
  5. BMC Cancer. 2026 Oct 22. pii: 1272. [Epub ahead of print]26(1):
    Neutrophils alter the metabolic profile of a coculture model of triple-negative breast cancer and stromal cells.
    Anna Thunström Salzer, Chloe Williams, Samuel Skoluda, Marios Stylianou, Jonathan D Gilthorpe, Constantin F Urban.
       BACKGROUND: Breast cancer is one of the most common cancer types. Triple-negative breast cancer (TNBC), one of the most lethal breast cancer subtypes, is characterized by substantial neutrophil accumulation in the tumor microenvironment (TME), although the impact of neutrophils on disease progression remains unclear.
    METHODS: To model interactions between cancer cells and stromal cells, we used a coculture system combining a TNB Ccell line with breast fibroblasts and exposed these cultures to neutrophils isolated from healthy donors.
    RESULTS: Coculture generated a pro-inflammatory environment, with increased levels of pro-inflammatory cytokines resembling cytokine profiles reported in cancer patients. Coculture-conditioned medium attracted neutrophils and activated them to produce reactive oxygen species (ROS). Coculture also altered metabolic activity, as measured by the Seahorse Extracellular Flux Assay, compared with the corresponding monocultures.
    CONCLUSIONS: Adding neutrophils to the coculture increased mitochondrial activity, suggesting that neutrophils may promote a metabolic shift in the coculture system: Together, our results support further investigation of neutrophil-driven changes in energy metabolism in TNBC microenvironments.
    Keywords:  Coculture; Inflammation; Mitochodrial activity; Neutrophils; Triple-negative breast cancer
    DOI:  https://doi.org/10.1186/s12885-026-17186-6
  6. J Biochem Mol Toxicol. 2026 Nov;40(11): e71123
    LINC01537 Regulates Malignant Phenotypes and Predicts Prognosis in Breast Cancer, and Its Bioinformatics Analysis.
    Yuetong Guo, Libo Shi.
      Breast cancer is a highly heterogeneous malignancy and constitutes one of the leading health threats to women globally. This study aimed to investigate the expression profile, clinical relevance, and molecular mechanisms of LINC01537 in breast cancer. Quantitative real-time PCR (qRT-PCR) was performed to detect the expression of LINC01537, miR-138-5p, and EZH2 in breast cancer tissues and cells. The Kaplan-Meier method was used for survival analysis, and forest plots were constructed to evaluate the prognostic significance of LINC01537. To explore the role of LINC01537 in BT549 and SK-BR-3 cells proliferation, apoptosis, migration, and invasion, LINC01537 was knocked down in BT549 and SK-BR-3 cells, followed by CCK-8, flow cytometry, and Transwell assays. A potential competing endogenous RNA (ceRNA) regulatory network was investigated through bioinformatics analysis, dual-luciferase reporter assays, and correlation analyses. Rescue experiments were further performed to confirm that LINC01537 modulates breast cancer progression via the miR-138-5p/EZH2 axis. LINC01537 was significantly upregulated in breast cancer tissues and cell lines compared to normal controls. High LINC01537 expression was associated with poor survival outcomes in patients. Knockdown of LINC01537 markedly suppressed proliferation, migration, and invasion, while promoting apoptosis in BT549 and SK-BR-3 cells. Mechanically, LINC01537 functioned as a ceRNA by sponging miR-138-5p, thereby abrogating its inhibitory effect on the target gene EZH2. Rescue experiments suggested that the inhibition of the malignant phenotypes of BT549 and SK-BR-3 cells caused by LINC01537 knockdown was rescued by miR-138-5p inhibition. The LINC01537/miR-138-5p/EZH2 ceRNA axis is involved in the progression of TNBC and HER2-positive breast cancer subtypes. In vitro data indicates that LINC01537 is a potential therapeutic candidate for TNBC and HER2-positive breast cancer, while further in vivo animal validation is required to support its translational application.
    Keywords:  EZH2; LINC01537; breast cancer; miR‐138‐5p; prognosis
    DOI:  https://doi.org/10.1002/jbt.71123
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