bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2026–03–08
eight papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. Large adipocytes increase vesicle-mediated lipid release and promote breast cancer malignancy.
  2. RECK attenuates CAF-mediated promotion of epithelial-mesenchymal transition in breast cancer.
  3. Common Signatures of Altered Gene Regulation and Invasiveness of Different Breast Cancer Cell Lines after Matrix Interface Crossing.
  4. ULK1-driven autophagy modulation alters tumor-promoting pathways in triple-negative breast cancer.
  5. Crosstalk between the extracellular matrix and breast stem cells in health and disease.
  6. Cancer metabolism in radiation sensitization: complementary roles of O-GlcNAc Transferase (OGT) and PARP1.
  7. Crosstalk between mitophagy and breast cancer: mechanisms of action and clinical applications.
  8. PANX1-mediated NLRP3 inflammasome activation promotes an adaptive doxorubicin resistance through IL-1β signaling in breast cancer.
  1. Cell Rep. 2026 Mar 05. pii: S2211-1247(26)00139-7. [Epub ahead of print]45(3): 117061
    Large adipocytes increase vesicle-mediated lipid release and promote breast cancer malignancy.
    Garrett F Beeghly, Irina Kopyeva, Jenny Deng, Marlee I Pincus, Rohan R Varshney, Dilip D Giri, Domenick J Falcone, Michael C Rudolph, Marc A Antonyak, Neil M Iyengar, Claudia Fischbach.
      Primary adipocytes exhibit striking variability in size, yet the functional consequences of adipocyte hypertrophy remain unclear due to insufficient experimental approaches to control for cell size. Here, we establish methods to culture large and small primary adipocytes isolated from the same adipose depot, enabling size-resolved analyses independent of systemic obesity. Using transcriptomic, lipidomic, and functional profiling across two mouse models of obesity, as well as human clinical samples, we show that adipocyte size-rather than body weight-drives distinct phenotypic cell states. Notably, large adipocytes increase extracellular vesicle-mediated lipid release. In coculture assays, this shift enhances lipid uptake, migration, and proliferation of breast cancer cells through fatty acid oxidation. Consistent with these findings, individuals with larger mammary adipocytes exhibit elevated fasting triglycerides independent of body mass index. Together, our results identify adipocyte size as a key determinant of adipose tissue function with implications for both metabolic disease and cancer progression.
    Keywords:  CP: cancer; CP: metabolism; adipocyte; adipose tissue; breast cancer; extracellular vesicles; hypertrophy; lipid metabolism; obesity; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2026.117061
  2. Biochem Biophys Res Commun. 2026 Feb 24. pii: S0006-291X(26)00262-7. [Epub ahead of print]810 153498
    RECK attenuates CAF-mediated promotion of epithelial-mesenchymal transition in breast cancer.
    Nada H Hussein, Mahadi Hasan, Renata Akhmetzianova, Hai Yu, Susumu Kohno, Takiko Daikoku, Akira Orimo, Chiaki Takahashi.
      Cancer associated fibroblasts (CAFs) play pivotal roles in modulating behaviors of tumor cells through various mechanisms. Here we analyzed a pair of fibroblastic cells derived from stromal tissue of breast cancer (BC-CAFs) or corresponding normal mammary microenvironment (NMFs). We found that the reversion-inducing cysteine-rich protein with Kazal motif (RECK) was highly expressed only in NMFs. Conditioned media derived from BC-CAFs enhanced epithelial-mesenchymal transition (EMT) in breast cancer cells significantly stronger than NMFs. Similarly, BC-CAFs induced EMT in co-injected breast cancer cells when xenografted into immune-compromised mice. These activities of BC-CAFs were significantly suppressed by RECK overexpression. BC-CAFs exhibited higher rate of active/latent TGF-β1 and active/pro-MMP-2. Induction of RECK in BC-CAFs significantly antagonized EMT induction with diminished activation of TGF-β1 and pro-MMP-2. Inversely, depletion of RECK in NMFs promoted EMT with enhancement of TGF-β1 and pro-MMP2 activation. BC-CAFs express higher level of histone deacetylase 1/2 (HDAC-1/2). Multiple HDAC inhibitors induced RECK in BC-CAFs with concomitant decrease in TGF-β 1and pro-MMP2 activation and ability to induce EMT. BC-CAFs exhibited higher histone acetylation in the promoter of RECK. These findings suggest that RECK ectopic expression in BC-CAFs suppresses TGF-β1 maturation by inhibiting pro-MMP-2 activation thereby attenuates EMT and that RECK promoter deacetylation occurs in fibroblasts associated with developing breast cancer. HDAC inhibitors may exhibit therapeutic efficacy in breast cancer by inducing RECK in BC-CAFs.
    Keywords:  Breast cancer (BC); Cancer-associated fibroblasts (CAFs); Epithelial-mesenchymal transition (EMT); Histone deacetylase 1 (HDAC1); Matrix metalloproteinase-2 (MMP-2); Reversion-inducing cysteine-rich protein with Kazal motifs (RECK); Transforming growth factor-β1 (TGF-β1)
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153498
  3. Adv Healthc Mater. 2026 Mar 05. e05616
    Common Signatures of Altered Gene Regulation and Invasiveness of Different Breast Cancer Cell Lines after Matrix Interface Crossing.
    Cornelia Clemens, Hannah Trampert, Nataliia Kotsiuba, Tilo Pompe.
      Interfaces between dense tumor tissue and surrounding more porous healthy tissue have been shown to trigger aggressive phenotypes in transmigrating MDA-MB-231 breast cancer cells, promoting directional migration, proliferation, and chemoresistance. Here, we show that such interface-instructed phenotype switching represents a common feature across triple-negative breast cancer (TNBC) cell lines, highlighting the potential for targeting these matrix interfaces in therapeutic approaches. Using a biomimetic collagen I interface model, we compared the different breast cancer cell lines, namely, MDA-MB-231, SUM159PT, and Hs578T, during the transmigration process. The interface-induced trigger of invasiveness was more pronounced in MDA-MB-231 and SUM159PT cells. RNA sequencing revealed shared transcriptional response in all three cell lines, with 228 commonly regulated genes and enrichment of pathways linked to cell cycle, chromatin organization, and DNA repair. Differences in pathway activation reflected the baseline characteristics of the three cell lines. Together, the results demonstrate that the topological and mechanical stimuli of tissue interfaces in general induce transcriptional reprogramming in TNBC cells with features of higher aggressiveness.
    Keywords:  cell migration; extracellular matrix interfaces; invasiveness; phenotype switching; transcriptomic reprogramming; triple‐negative breast cancer
    DOI:  https://doi.org/10.1002/adhm.202505616
  4. Med Oncol. 2026 Mar 03. pii: 163. [Epub ahead of print]43(4):
    ULK1-driven autophagy modulation alters tumor-promoting pathways in triple-negative breast cancer.
    Merve Gulsen Bal Albayrak, Sevinc Yanar, Tuğcan Korak, Gurler Akpinar, Murat Kasap.
      Triple-negative breast cancer (TNBC) is an aggressive subtype with limited targeted therapies and poor prognosis. Unc-51-like kinase 1 (ULK1), a central regulator of autophagy, has emerged as a potential therapeutic node in cancer but remains poorly understood in TNBC. Here, we investigated the proteomic consequences of pharmacological ULK1 modulation in MDA-MB-231 TNBC cells. Cells were treated with the ULK1 activator LYN-1604 or inhibitor MRT68921 at EC₅₀ concentrations. Autophagic activity, validated through LC3B immunoblotting and fluorescence microscopy, increased under both treatments. Quantitative label-free LC-MS/MS proteomics prioritized 182 and 196 candidate differentially abundant proteins in response to LYN-1604 and MRT68921, respectively. ULK1 activation primarily altered transcriptional regulation and suppressed translation, whereas inhibition was associated with enrichment of immune-related pathway and vesicle-mediated transport. Five proteins consistently downregulated across both treatments (PSIP1, AGO2, MORF4L1, HNRNPC, and SETD2) were prioritized as candidate hubs based on shared regulation across perturbations and network ranking using CytoHubba/MCC. These candidates mapped to autophagy-associated pathway modules/terms related to MET-FAK signaling, extracellular matrix-related processes, and mitochondrial Ca²⁺ handling/transport. These findings suggest that ULK1 modulation, regardless of direction, associated with proteomic changes in pathways linked to tumor-promoting networks. Our study provides a comprehensive proteomic framework linking ULK1 perturbation to transcriptional, immune, and epigenetic regulation, and highlights downstream effectors as candidate targets for future functional and translational validation in TNBC.
    Keywords:  Autophagy; Hub gene analysis; Immune signaling pathways; Label-free LC-MS/MS; Proteomics; Triple-negative breast cancer (TNBC); ULK1
    DOI:  https://doi.org/10.1007/s12032-026-03274-x
  5. FEBS J. 2026 Mar 03.
    Crosstalk between the extracellular matrix and breast stem cells in health and disease.
    Giuliana Siragusa, Lorena Fernandez-de-Larrea, Niels Meesters, Maria dM Vivanco.
      Female breast development occurs at puberty and undergoes many cyclic changes under normal physiological conditions, like pregnancy, lactation and involution. The breast epithelium is surrounded by a heterogenous stroma that encompasses various cell types, including fibroblasts, immune cells, adipocytes, endothelial cells and an extracellular matrix (ECM). The ECM is a complex molecular meshwork composed of a variety of matricellular proteins and ECM remodelling enzymes, including proteases. Dynamic remodelling of the ECM is fundamental to the organisation and function of the mammary gland and is associated with stemness. It is often aberrantly regulated in breast cancer, which still has the highest incidence and mortality rates in women worldwide. Improved models could contribute to a better understanding of cell-matrix interactions, including in the stem cell niche, and ECM remodelling in health and tumorigenesis. This could lay the groundwork for therapeutic strategies that also target the breast cancer ECM for improved precision medicine tools.
    Keywords:  ECM; breast; breast cancer; proteases; stem cells
    DOI:  https://doi.org/10.1111/febs.70449
  6. J Cell Sci. 2026 Mar 04. pii: jcs.264322. [Epub ahead of print]
    Cancer metabolism in radiation sensitization: complementary roles of O-GlcNAc Transferase (OGT) and PARP1.
    Elena Efimova, Yue Liu, Sera Averbek, SeokGyeong Choi, Sojung Ha, Natalia Ricco, Isabelle Lomeli, Evalds Viguls, Woo-Young Kim, Stephen J Kron.
      For double-strand breaks (DSBs) formed by radiation, onset of 5' to 3' end resection is a deciding factor in repair pathway choice, favoring homologous recombination (HR) over non-homologous end-joining (NHEJ). Studying HR-proficient MCF7 breast cancer cells, we confirmed a role for PARP1 in promoting DSB repair and limiting resection stress and identify the hexosamine biosynthetic pathway (HBP)-dependent post-translational modification O-GlcNAcylation as an independent regulator. Using pharmacological and genetic perturbations of O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), we showed that O-GlcNAcylation can limit end resection as measured by BrdU and RPA staining, recruitment of HR proteins BRCA1 and RAD51, and accumulation of cytosolic DNA in S/G2-phase cells. These effects were independent of PARP1 but required the histone methyltransferase EZH2. Loss of OGT or EZH2 phenocopied PARP inhibition, leading to hyperresection after irradiation. The OGA inhibitor PUGNAc suppressed hyperresection due to PARP1 knockout while PARP inhibitor veliparib exacerbated defects in OGT- or EZH2-deficient cells. In each case, increased resection correlated with cytosolic DNA accumulation, suggesting a link to inflammatory signaling. These findings implicate the Warburg effect, via the HBP and O-GlcNAcylation, in favoring NHEJ over HR and suggest that disrupting EZH2 may sensitize HR-proficient tumor cells to radiation via resection-dependent mechanisms. Our results highlight the potential of targeting cancer-associated metabolic reprogramming to overwhelm HR repair and drive resection stress. Combining PARP inhibition with blockade of O-GlcNAcylation or EZH2 may offer a strategy to radiosensitize proliferating, HR-proficient cancers while sparing non-cycling normal tissues.
    Keywords:  DNA end resection; EZH2; Hexosamine biosynthetic pathway; O-GlcNAcylation; PARP; Radiosensitization
    DOI:  https://doi.org/10.1242/jcs.264322
  7. J Cancer Res Clin Oncol. 2026 Feb 28. pii: 55. [Epub ahead of print]152(2):
    Crosstalk between mitophagy and breast cancer: mechanisms of action and clinical applications.
    Kun Rui, Jingjing Qiu, Minghao Li, Jianjun Huang, Tao Wang, Kai Yin.
      Mitophagy, a key mechanism of selective autophagy, maintains cellular homeostasis by removing dysfunctional mitochondria, and its dysregulation is closely associated with tumor initiation and progression. As breast cancer remains one of the most prevalent malignancies among women worldwide, its heterogeneity and therapeutic resistance have prompted growing interest in identifying novel molecular targets. Emerging evidence indicates that mitophagy plays a dual role in breast cancer development, metastasis, and treatment resistance by regulating energy metabolism, oxidative stress, and cell-fate decisions. This review systematically summarizes the molecular mechanisms of mitophagy and its dynamic regulatory networks in breast cancer. Further, it discusses emerging mitophagy-targeted therapeutic strategies, aiming to provide a theoretical foundation for the precision treatment of breast cancer.
    DOI:  https://doi.org/10.1007/s00432-026-06434-8
  8. Cancer Lett. 2026 Feb 27. pii: S0304-3835(26)00150-3. [Epub ahead of print]645 218387
    PANX1-mediated NLRP3 inflammasome activation promotes an adaptive doxorubicin resistance through IL-1β signaling in breast cancer.
    Chenxuan Yang, Jiaxiang Liu, Xiyu Kang, Zhanyu Wang, Qingyao Shang, Jiaxian Yue, Guangyu Li, Xubin Dong, Chao Shang, Tianxiao Wang, Dongmin Yang, Xin Wang.
       BACKGROUND: Acquired resistance to chemotherapy is a major clinical obstacle in breast cancer treatment. While inflammasome activation is often induced during chemotherapy, its role in regulating therapeutic resistance remains poorly understood. Pannexin-1 (PANX1), a transmembrane channel protein, is a potential regulator of inflammation, but its function in chemoresistance has not been explored.
    METHODS: We used a multifaceted approach combining single-cell/spatial transcriptomics of patient cohorts and functional validation. The role of PANX1 was investigated using pharmacological inhibitors and genetic knockdown cell lines and animal models.
    RESULTS: High PANX1 expression correlates with worsened overall survival (log-rank p = 0.012), genomic instability, and chemoresistance in breast cancer patients. Mechanistically, doxorubicin (DOX) treatment triggers a PANX1-dependent activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome and downstream maturation of interleukin-1β (IL-1β). Pharmacological or genetic inhibition of PANX1 re-sensitized resistant breast cancer cells to DOX both in vitro and in vivo. This effect was mechanistically reversed by the addition of exogenous IL-1β, identifying it as the key downstream effector of resistance. In an external neoadjuvant chemotherapy cohort, the interaction of PANX1 and NLRP3 expression was validated to be a predictor for the probability of achieving a pathological complete response (pCR) to DOX-based treatment.
    CONCLUSIONS: Our study delineates a critical mechanism of adaptive chemoresistance in breast cancer orchestrated by the PANX1-NLRP3-IL-1β signaling. We provide a preclinical rationale for PANX1 not only as a biomarker for pCR prediction in patients receiving DOX-based neoadjuvant chemotherapy, but also as a targetable molecule to resensitize DOX-resistant tumors.
    Keywords:  Breast cancer; Chemoresistance; Doxorubicin; IL-1β; NLRP3 inflammasome; PANX1
    DOI:  https://doi.org/10.1016/j.canlet.2026.218387
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