bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2026–05–17
eight papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. Obesity, Inflammation, and Tumor Microenvironment in Three-Dimensional Models of Breast Cancer.
  2. Comprehensive analysis suggests CRIF1 is a potential target in breast cancer associated with prognosis and immune infiltration.
  3. CAF-derived exosomes drive trastuzumab resistance in HER2-positive breast cancer via YAP-USP8-HER2 axis activation.
  4. High-fat diet reshapes microbial interactions to promote breast cancer stemness via Streptococcus mutans-induced leucine accumulation.
  5. Full-Length Transcriptome Profiles Reveal the Molecular Function of Oncogene HNRNPA2B1 in Triple-Negative Breast Cancer.
  6. Disrupting oncogenic signaling in triple negative breast cancer: The interplay of Cx43, Pyk2, and Src in MDA-MB-231 cells.
  7. Endocrine therapy reprogramming of breast cancer facilitates metastatic escape via upregulation of P-Rex1/Rac1 signalling.
  8. Novel Selective Anticancer Effect of Epididymis-Derived Extracellular Vesicles Against HCC38 and MCF-7 Breast Cancer Cell Lines.
  1. Cells. 2026 Apr 24. pii: 761. [Epub ahead of print]15(9):
    Obesity, Inflammation, and Tumor Microenvironment in Three-Dimensional Models of Breast Cancer.
    Yarely M Salinas-Vera, Yussel Pérez-Navarro, Jonathan Puente-Rivera, María Elizbeth Álvarez-Sánchez, César López-Camarillo.
      Obesity is recognized as a risk factor for breast cancer development and progression. Adipocytes exert their oncogenic effects through complex and interconnected biological mechanisms that encompass metabolic dysfunction, chronic low-grade inflammation, and systemic endocrine alterations. Herein, we reviewed the current evidence explaining how obesity induces a state that reprograms adipose tissue and remodels the breast cancer tumor microenvironment (TME). We first discuss the systemic and local mechanisms linking obesity to inflammation and how these alterations reshape the functional organization of the mammary gland. Then, we discuss how the chronic exposure to tumor-derived signals, together with the altered metabolic state of obese adipose tissue, induces a functional reprogramming of adipocytes, giving rise to so-called cancer-associated adipocytes (CAAs), which actively contribute to tumor progression. Also, the strengths and limitations of biological models to study the crosstalk between adipocytes and tumor cells, including two-dimensional (2D) monolayers and three-dimensional (3D) cell cultures, as well as animal models, are discussed. Special emphasis is placed on 3D co-culture models, which more accurately reproduce spatial organization, direct cell-cell contact, and diffusion dynamics, providing a more physiologically relevant environment for studying how obesity and inflammation reshape the TME in breast cancer. Finally, we highlight the limitations of conventional experimental models and review recent advances in 3D-based platforms, emphasizing their mechanistic insights and translational potential.
    Keywords:  3D culture; adipocytes; breast cancer; co-culture; inflammation; obesity; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells15090761
  2. Ann Med. 2026 Dec;58(1): 2593151
    Comprehensive analysis suggests CRIF1 is a potential target in breast cancer associated with prognosis and immune infiltration.
    Yongping Li, Jie Liu, Ming Zhong, Weiping Yu, Hongbo Zhu, Xueting Wang, Hao Yuan.
       BACKGROUND: CRIF1 is a multifunctional factor that regulates cell biological processes such as the cell cycle, cell proliferation, and energy metabolism, and it is a new molecule that contributes to the poor prognosis of many malignancies. However, its involvement in breast cancer development is not fully known.
    MATERIALS AND METHODS: To investigate the relationship between CRIF1 expression, prognosis, and clinical characteristics using The Cancer Genome Atlas (TCGA-BRCA). The relationship between CRIF1 expression and the immunological microenvironment was investigated using CIBERSORT, ESTIMATE. Breast tissue and CRIF1 expression were validated by IHC. A tiny interfering plasmid was designed to transiently transfect breast cancer cell lines, and proliferation-related functional tests were carried out. The effect of sh CRIF1 on tumor formation was confirmed using a subcutaneous tumor experiment in naked mice.
    RESULTS: We discovered that CRIF1 was highly elevated in breast cancer tissues and associated with a poor prognosis. CRIF1 stimulates breast cancer cell proliferation, migration, and invasion. Knockdown decreased PI3K/AKT/mTOR signaling, which boosted autophagy activity. Immune infiltration research revealed that patients with high CRIF1 expression had higher CD8+ T cell expression but reduced macrophage M2 expression.
    CONCLUSION: Upregulation of CRIF1 in breast cancer cells enhances malignant behavior, which may be mediated by PI3K/AKT/mTOR signaling and is linked to cellular autophagy.
    Keywords:  CRIF1; biomarker; breast cancer; immunotherapy; prognosis
    DOI:  https://doi.org/10.1080/07853890.2025.2593151
  3. Breast Cancer Res. 2026 May 15.
    CAF-derived exosomes drive trastuzumab resistance in HER2-positive breast cancer via YAP-USP8-HER2 axis activation.
    Weijia Yu, Li Jiang.
       BACKGROUND AND OBJECTIVE: Cancer-associated fibroblasts (CAFs), critical constituents of the tumor microenvironment, promote tumor progression and therapeutic resistance through exosome secretion. However, the mechanisms by which CAF-derived exosomes contribute to trastuzumab resistance in HER2-positive breast cancer remain unclear. This study investigated whether CAF-derived exosomes activate the YAP-USP8 axis to stabilize HER2 and induce trastuzumab resistance.
    METHODS: Primary CAFs and normal fibroblasts (NFs) were isolated from HER2-positive breast cancer specimens, and exosomes were characterized by TEM, nanoparticle tracking analysis, and immunoblotting of exosomal markers. HER2-positive breast cancer cells (HCC1954 and BT-474) were treated with CAF- or NF-derived exosomes in vitro. Mechanistic studies were performed mainly in HCC1954 cells, whereas BT-474 cells were used for validation. Cargo dependency was assessed using RNase/Proteinase K protection assays, and YAP pathway involvement was examined using Verteporfin. In vivo tumor growth was evaluated using xenograft models.
    RESULTS: CAF-derived exosomes reduced LATS1 and YAP phosphorylation (p < 0.001), enhanced nuclear YAP accumulation, and upregulated USP8 transcription, leading to HER2 stabilization (P < 0.001). Membrane disruption abolished Hippo suppression, indicating dependence on intravesicular cargo. CAF-exo treatment increased proliferation, elevated trastuzumab IC50, reduced apoptosis, and accelerated tumor growth in vivo (all p < 0.001). These effects were reproduced in BT-474 cells and were reversed by YAP or USP8 silencing. Pharmacological inhibition of YAP similarly restored trastuzumab sensitivity. TCGA-BRCA analysis revealed positive correlations between YAP1 and USP8, and between USP8 and ERBB2, supporting the molecular relevance of this axis.
    CONCLUSION: This study identified a novel CAF-exosome-YAP-USP8-HER2 signaling axis that drives trastuzumab insensitivity in HER2-positive breast cancer. Intervening in this pathway may represent a potential treatment approach to counteract microenvironment-induced chemoresistance.
    Keywords:  Cancer-associated fibroblasts; Exosomes; HER2; Trastuzumab resistance; USP8; YAP
    DOI:  https://doi.org/10.1186/s13058-026-02288-7
  4. Breast Cancer Res. 2026 May 11.
    High-fat diet reshapes microbial interactions to promote breast cancer stemness via Streptococcus mutans-induced leucine accumulation.
    Chao Cheng, Fahu Yuan, Jincheng Li, Yixian Fan, Yang Liu, Quan Zhang, Yanjun Lu, Lei He.
       BACKGROUND: Obesity and high-fat diet (HFD) are established risk factors for breast cancer, but the mechanisms by which dietary-induced gut microbiota alterations influence cancer progression are not fully understood. The interplay between microbial composition, metabolites, and cancer progression warrants further exploration.
    METHODS: We employed Mendelian randomization (MR) and Bayesian colocalization analyses based on genome-wide association studies (GWAS) to identify gut microbial genera causally linked to breast cancer risk. Multi-omics, including 16S rRNA sequencing, fecal metabolomics and RNA-seq, were performed to depict HFD-induced microbial and metabolic shifts in breast cancer-bearing mice. In vitro co-culture systems and in vivo murine models examined interactions between Roseburia intestinalis (R. intestinalis) and Streptococcus mutans (S. mutans) under HFD conditions. Functional assays, including immunofluorescence, qRT-PCR, probe-based assays and fluorescent in situ hybridization, and flow cytometry, evaluated cancer stemness, bacterial colonization, and the impact of leucine metabolism.
    RESULTS: MR analysis revealed Roseburia as a potential causal microbial risk factor for breast cancer, with colocalized genes enriched in fatty acid metabolism. HFD feeding promoted the co-occurrence of R. intestinalis and S. mutans, facilitating S. mutans intratumoral colonization and consequent leucine accumulation in the tumor microenvironment (TME). S. mutans-derived leucine robustly enhanced breast cancer cell proliferation and stemness, as evidenced by increased tumor sphere formation and upregulation of CD44, CD133, and SOX2. Functional blockade of leucine transport with BCH attenuated S. mutans-mediated tumor growth and limited tumor-associated macrophage activation in vivo.
    CONCLUSIONS: This study reveals that HFD-induced reshaping of microbial interactions, particularly a commensal-like interaction between S. mutans and R. intestinalis, is associated with leucine accumulation in the TME, thereby supporting breast cancer stemness and progression. Targeting S. mutans-mediated leucine accumulation represents a promising strategy for therapeutic intervention in obesity-related breast cancer. Our findings highlight the pivotal role of dietary-microbiota crosstalk in modulating the TME and cancer stemness.
    Keywords:   Roseburia intestinalis ; Streptococcus mutans ; Breast cancer; Cancer stemness; Gut microbiota; High-fat diet; Leucine metabolism
    DOI:  https://doi.org/10.1186/s13058-026-02297-6
  5. Cancer Med. 2026 May;15(5): e71921
    Full-Length Transcriptome Profiles Reveal the Molecular Function of Oncogene HNRNPA2B1 in Triple-Negative Breast Cancer.
    Lina Yi, Yongtao Li, Jianghua Ou.
      Triple negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with the worst prognosis. Heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1), a member of the RNA-binding protein (RBP) hnRNPs family, is aberrantly expressed in various human cancers, serving as a marker of poor prognosis and acting as an oncogene. However, its expression, biological function, and molecular mechanism in TNBC remain unclear. In this study, we examined the expression of HNRNPA2B1 in one normal mammary epithelial cell line (MCF10A) and four TNBC cell lines (HS 578 T, BT-20, MDA-MB-468, and MDA-MB-231). We conducted in vitro and in vivo knockdown experiments to compare the growth ability, gene expression profiles, and alternative splicing patterns of TNBC cells with HNRNPA2B1 knockdown to those of control cells. Our results demonstrated that HNRNPA2B1 is overexpressed in triple-negative breast cancer tissues and cell lines. Knockdown of HNRNPA2B1 significantly inhibited proliferation and metastasis while promoting apoptosis in TNBC cells. Mechanistically, HNRNPA2B1 knockdown broadly impacted the expression and alternative splicing of genes associated with cell migration, proliferation, and apoptosis. Using Nanopore long-read sequencing, we further revealed that HNRNPA2B1 regulates gene expression in TNBC cells through the modulation of alternative polyadenylation. These findings highlight the critical role of HNRNPA2B1 in TNBC progression, providing new insights into its mechanisms and potential therapeutic applications.
    Keywords:  HNRNPA2B1; RNA‐binding protein; alternative polyadenylation; alternative splicing; breast cancer; gene expression
    DOI:  https://doi.org/10.1002/cam4.71921
  6. Cell Tissue Res. 2026 May 13. pii: 11. [Epub ahead of print]404(2):
    Disrupting oncogenic signaling in triple negative breast cancer: The interplay of Cx43, Pyk2, and Src in MDA-MB-231 cells.
    Li Zheng, Gaelle Spagnol, Paras Gupta, Paul L Sorgen.
      Triple-negative breast cancer (TNBC) lacks targeted therapies and is driven by dysregulated signaling networks that promote migration, invasion, and survival. Connexin43 (Cx43), a gap junction protein essential for maintaining normal mammary epithelial homeostasis, becomes aberrantly phosphorylated and mislocalized in breast cancer, contributing to disease progression. Because the tyrosine kinases Pyk2 and Src regulate Cx43 and multiple pro-tumorigenic pathways, we investigated whether their combined inhibition could suppress malignant behaviors in TNBC. In MDA-MB-231 cells, the Pyk2 inhibitor PF4618433 and Src inhibitor Saracatinib modestly reduced metabolic activity at high concentrations; however dual treatment produced a dose-dependent and synergistic reduction in viability. In migration and invasion assays, each inhibitor reduced motility, however dual inhibition produced the strongest suppression. Cx43 knockdown impaired baseline migration and invasion and altered the response to Pyk2/Src inhibition, indicating that Cx43 modulates sensitivity to these agents. PF4618433 increased Cx43 plaque formation without changing total protein levels. Mechanistically, Pyk2 inhibition reduced phosphorylation of Cx43 at Y265 and decreased levels of TAZ, p-Erk1/2, p130Cas, and Notch1, whereas Src inhibition only reduced p-Erk1/2. Dual treatment did not further decrease these signaling nodes but nonetheless produced stronger functional inhibition of viability and motility, and the shared regulation of p-Erk1/2 by Pyk2 and Src may help explain how compensatory Pyk2 activation limits the effectiveness of Src-targeted therapies. Together, these findings show that coordinated Pyk2 and Src inhibition restores Cx43 organization and disrupts multiple malignant traits in TNBC cells, supporting this combination as a promising therapeutic strategy.
    Keywords:  Breast cancer; Cx43; Phosphorylation; Pyk2; Src
    DOI:  https://doi.org/10.1007/s00441-026-04074-5
  7. Nat Commun. 2026 05 11. pii: 3042. [Epub ahead of print]17(1):
    Endocrine therapy reprogramming of breast cancer facilitates metastatic escape via upregulation of P-Rex1/Rac1 signalling.
    Kristine J Fernandez, Ghazal Sultani, Max Nobis, Brian Gloss, Leila Eshraghi, Amy E McCart Reed, Sarah Alexandrou, Christine Lee, Daniel L Roden, Emily I Jones, Maryam Hasha Simad, Ewan K A Millar, Nenad Bartonicek, Samantha R Oakes, Fatima Valdes-Mora, Yolanda Colino-Sanguino, Ellie T Y Mok, Hannah L Williams, Jamie R Kutasovic, Margaret C Cummings, Janett Stoehr, Victoria Lee, Kate Harvey, Sunny Wu, Sunil R Lakhani, Peter T Simpson, Thomas R Cox, Lisa M Ooms, Christina A Mitchell, Rob Salomon, Alexander Swarbrick, David Gallego-Ortega, Elgene Lim, Paul Timpson, C Elizabeth Caldon.
      The estrogen receptor (ER) drives growth in most breast cancers. Endocrine therapy reduces recurrence, however around 30% of cancers relapse. Many recurrences occur years later, with slowly proliferating, hard-to-treat disease. To study this, we generate slow-growing resistant cells that form small primary tumours but readily metastasise. Single-cell RNA sequencing (scRNAseq) reveals that endocrine therapy reprograms these cells, notably upregulating the Rac1 signalling component P-Rex1. We find in clinical cohorts that P-Rex1 is high in ER+ breast cancer, including in late recurrent disease. Intravital imaging demonstrates that Rac1 signalling is active in ER+ cells following endocrine therapy. Targeting the Rac1 pathway with small molecule inhibitors (NSC23766, R-ketorolac) reduces survival and motility in resistant cells, inhibits in vivo Rac1 activity, and reduces tumour burden when combined with tamoxifen in a drug-refractory patient derived xenograft model. This work identifies the P-Rex1/Rac1 axis as a potential therapeutic target for late recurring ER+ breast cancer.
    DOI:  https://doi.org/10.1038/s41467-026-70683-x
  8. Int J Mol Sci. 2026 Apr 27. pii: 3870. [Epub ahead of print]27(9):
    Novel Selective Anticancer Effect of Epididymis-Derived Extracellular Vesicles Against HCC38 and MCF-7 Breast Cancer Cell Lines.
    Razi Zoabi, Zenab Ali Saleh, Elias Issaq, Etedal Morad, Reem Miari, Hanan Taha, Ahmad Kadriya, Abraham O Samson, Mizied Falah.
      Prevalent cancers primarily include breast, lung and bronchus, prostate, and colorectal cancers. In contrast, cancer of the epididymis is very rare, and we propose that this tissue could carry inherent anticancer components, in particular, small extracellular vesicles (EVs) with antineoplastic properties. All cell types release extracellular vesicles (EVs) into their intercellular space, which act in the crosstalk required to achieve homeostasis. Among these, small EVs, which are membrane-bound vesicles with an average diameter of 30-200 nm, can transfer cell-specific cargo, such as lipids, proteins, DNA and RNA, which can be selectively received by neighboring or distant cells, and trigger specific cell processes, such as growth, division, or apoptosis. Here, we isolated small EVs from epididymis tissue, and examined their effect on morphology, viability, apoptosis, cell cycle phases, and certain gene and protein expression levels, particularly of the pro-apoptotic p53 protein, in HCC38 and MCF-7 breast cancer cell lines, as well as in a normal fibroblast cell line. The various analyses demonstrated effects on breast cancer cells but not on normal cells. Specifically, epididymis-derived EVs (Ep-EVs) selectively induced apoptosis and cell cycle arrest in cancer cells, while normal cells were unaffected. Moreover, the relative uptake of Ep-EVs in HCC38 and MCF-7 breast cancer cells was significant, indicating a direct association between vesicle internalization and the biological response. Taken together, these findings demonstrate a solid experimental foundation supporting the therapeutic potential of Ep-EVs in breast cancer, with promising implications for their development as a broader anticancer platform.
    Keywords:  apoptosis; breast cancer; epididymis-derived EVs; extracellular vesicles; p53
    DOI:  https://doi.org/10.3390/ijms27093870
This page is being maintained by Thomas Krichel. It was last updated on 2026‒05‒17 at 2:09.