bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2026–03–15
eight papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. CHD1 is a synthetic lethal vulnerability in MYC-driven breast cancer.
  2. The SDC1-ENO1 Axis in Cancer-Associated Fibroblasts Generates a Lactate-Rich Microenvironment that Drives Tumor Radioresistance.
  3. [FGFR1 mRNA expression in different molecular subtypes of breast cancer].
  4. Effect of Healthy and Tumor-Associated Breast Adipose Tissue on Breast Cancer Cell Migration and Activation.
  5. Interplay of Interleukin-1β and Curcumin on VEGF Expression in Breast Cancer Cells.
  6. Reprogramming innate immunity to overcome endocrine resistance in estrogen receptor-positive breast cancer.
  7. In vivo imaging of metabolic heterogeneity across three endpoints relevant to aggressive breast cancer.
  8. An oncogenic, truncated FGFR1 variant cooperates with SPFQ/NONO to regulate gene transcription in FGFR1-driven leukaemia.
  1. Oncogene. 2026 Mar 07.
    CHD1 is a synthetic lethal vulnerability in MYC-driven breast cancer.
    Brandon Cho, Giacomo Furlan, Peter Lin, Mélissa Shen, Kirti Mittal, Andrew Mazzanti, Linda Z Penn, Miguel Ramalho-Santos.
      The MYC transcription factor is a key regulator of growth during development and a potent cancer driver when its expression is dysregulated. Strategies to inhibit MYC oncogenic activity would mark a significant advance, but decades of efforts to target MYC directly have not been fruitful. Understanding how MYC drives transformation and tumor growth may provide new therapeutic avenues in a variety of cancers. By intersecting two independent genome-wide screens, we identified loss of the chromatin remodeler Chromodomain-Helicase DNA-binding 1 (CHD1) as a potential synthetic lethal target in MYC-driven breast cancer. Knockdown of CHD1 in a xenograft model of MYC-driven breast cancer suppresses tumor growth in vivo. In tissue culture models, we found that knockdown of CHD1 suppresses cell proliferation and induces cell death, specifically when MYC is overexpressed. Mechanistically, we found that CHD1 is required to maintain an open chromatin landscape and a transcriptional program associated with cancer progression in MYC overexpressing breast cells. Follow-up experiments indicate that this synthetic lethality may arise from nucleolar stress and p53 activation. These findings provide new insights on the chromatin-level regulation of MYC-driven breast cancer and uncover CHD1 as a novel synthetic vulnerability and potential therapeutic target.
    DOI:  https://doi.org/10.1038/s41388-026-03709-9
  2. Cancer Res. 2026 Mar 11.
    The SDC1-ENO1 Axis in Cancer-Associated Fibroblasts Generates a Lactate-Rich Microenvironment that Drives Tumor Radioresistance.
    Xupeng Hou, Moran Chen, Xiaojing Guo, Yongjie Xie, Lin Li, Xiaoya Tang, Ziyun Liu, Wenna Jiang, Weiwei Bai, Hongxia Sun, Xiaoli Yu, Jihui Hao, Jing Liu.
      Radiotherapy resistance remains a major barrier to effective treatment of triple-negative breast cancer (TNBC), highlighting the need to identify mechanisms driving resistance. Here, we identified SDC1 as a pivotal mediator of cancer-associated fibroblast (CAF)-induced radioresistance in breast cancer. SDC1 bound the TIM barrel domain of the glycolytic enzyme ENO1, preventing FBXW7-mediated degradation and driving aerobic glycolysis and lactate accumulation. The resulting lactate-rich microenvironment not only promoted tumor stemness but also significantly impaired the cytotoxic functions of both NK cells and CD8⁺ T cells. Pharmacologic inhibition of ENO1 or lactate export restored radiosensitivity. Targeting SDC1⁺ CAFs with the antibody-drug conjugate indatuximab ravtansine (BT062) synergized with radiotherapy in vivo, markedly reducing tumor burden, depleting stem-like tumor cells, and remodeling the immune microenvironment. These findings define a CAF metabolic program that fuels tumor stemness and rewires the immune microenvironment to confer radioresistance, supporting the therapeutic targeting of SDC1⁺ CAFs in TNBC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-3806
  3. Zhonghua Bing Li Xue Za Zhi. 2026 Mar 08. 55(3): 229-234
    [FGFR1 mRNA expression in different molecular subtypes of breast cancer].
    M L Liu, S F Wu, Y Y Liu, H X Zhang, D C Zhao, X Huang, J Lian, X Zeng.
      Objective: To investigate FGFR1 mRNA expression and gene characteristics in breast cancer tissue. Methods: Breast cancer samples from 45 female patients (10 HER2-positive, 15 triple-negative and 20 HR-positive/HER2-negative cases) were collected from Peking Union Medical College Hospital between December 2022 and January 2024. FGFR1 mRNA expression was identified using reverse transcription droplet digital PCR, and the FGFR1 gene characteristics was analyzed from 30 samples by fluorescence in situ hybridization. Results: In the group of HER2-positive, 2 cases (2/10) of high FGFR1 mRNA expression and one case (1/7) of high FGFR1 gene amplification were found. Five tumors (5/15) with high FGFR1 mRNA expression, one (1/10) with gene amplification and one (1/10) with low-level amplification of FGFR gene were identified in triple-negative breast cancer. Among HR-positive/HER2-negative samples, high FGFR1 mRNA expressions were confirmed in 4 cases (4/20), with no FGFR1 gene amplification (0/13). Additionally, 3 cases (3/10) showed high FGFR1 mRNA expression in HER2-low expression (IHC 1+and IHC 2+/FISH-) samples. Conclusions: High FGFR1 mRNA expression is observed across different molecular subtypes of breast cancer. High-level FGFR1 gene amplification is uncommonly detected; therefore, further studies with large amount samples are required.
    DOI:  https://doi.org/10.3760/cma.j.cn112151-20250820-00567
  4. Cancers (Basel). 2026 Mar 08. pii: 868. [Epub ahead of print]18(5):
    Effect of Healthy and Tumor-Associated Breast Adipose Tissue on Breast Cancer Cell Migration and Activation.
    Iris L Holt-Kedde, Hetty Timmer-Bosscha, Frank A E Kruyt, Wendy Kelder, Bert van der Vegt, Mieke C Zwager, Carolien P Schröder, Marlous Arjaans.
       BACKGROUND: Obesity is a recognized risk factor for developing breast cancer (BC), but factors involved remain unclear. We investigated if breast adipose tissue from healthy women, BRCA1/2 mutation carriers and BC patients, can stimulate BC cell line migration and activation.
    METHODS: adipose tissue conditioned medium (ATCM), was prepared from breast adipose tissue from healthy subjects (naïve; group 1 (n = 20)), BRCA1/2 mutation carriers (group 2 (n = 22)) and BC patients (group 3 (n = 38)). ATCM effect on migration of BC cell lines MCF-7, SK-BR-3 and MDA-MB-231 was measured with xCELLigence (ACEA Biosciences, San Diego, CA, USA) cell migration assay. Activation of migration was determined by measuring filopodia activation. Migration and filopodia activation were related to body mass index (BMI) and BC subtypes. Luminex multiplex assay was performed to examine the secretory profile of adipose tissue.
    RESULTS: ATCM from group 1 induced migration and filopodia activation in MCF-7 and MDA-MB-231, but not in SK-BR-3. ATCM from group 2 induced filopodia activation but no migration. ATCM from group 3 induced less migration in MCF-7 than ATCM from group 1. Higher BMI was associated with increased ATCM-induced activation in MCF-7 (group 1) and MDA-MB-231 (group 2). ATCM from group 1 and 2 showed a metabolic secretory profile, whereas group 3 showed higher pro-angiogenic and inflammatory cytokines.
    CONCLUSIONS: This study shows that breast adipose tissue from healthy women, BRCA1/2 mutation carriers and BC patients, can stimulate BC cell line migration and activation. This effect is related to BC subtype and BMI. These data improve insight in adipose tissue as factor in BC development.
    Keywords:  BRCA; adipose tissue; breast cancer; conditioned medium; obesity
    DOI:  https://doi.org/10.3390/cancers18050868
  5. Oncol Res. 2026 ;34(3): 13
    Interplay of Interleukin-1β and Curcumin on VEGF Expression in Breast Cancer Cells.
    Norbert Nass, Atanas Ignatov, Thomas Kalinski.
       Objectives: Vascular endothelial growth factor (VEGF) regulates tumor vascularization in response to hypoxia and inflammatory signals. The polyphenol curcumin is supposed to interfere with inflammation-induced VEGF secretion and might therefore support anti-VEGF-based treatments. We aimed to investigate the interaction between curcumin and the inflammatory cytokine Interleukin-1β (IL-1β) for VEGF secretion in breast cancer cell lines representing major breast cancer subtypes.
    Methods: VEGF in cell cultures was detected by Western blot and enzyme-linked immunosorbent assay (ELISA). Kinase phosphorylation was investigated by Western blotting. Gene expressions were analyzed by correlation tests. VEGF was evaluated in a retrospective breast cancer cohort by immunohistochemistry. Survival analysis was performed by the Kaplan-Meier algorithm.
    Results: VEGF secretion and kinase signaling in response to IL-1β and curcumin varied significantly for the cell lines MCF-7 (Luminal A), SK-BR-3 (HER2/neu+), MDA-MB-231, and UACC-3199 (triple negative breast cancer). All cell lines increased VEGF secretion under hypoxia, but IL-1β increased VEGF secretion only in MCF-7 cells. Curcumin inhibited VEGF secretion in MDA-MB-231, but increased it in MCF-7 and UACC-3199 cells. Curcumin induced phosphorylation of extracellular signal-regulated kinase (ERK) and p38-mitogen-activated protein kinase (p38-MAPK). However, inhibitor experiments demonstrated that ERK was more important for VEGF secretion. In gene expression data from the METABRIC study, no clear correlation of hypoxia-induced factor (HIF1A), IL-1β, and VEGF mRNA expression was observed; however, a suggested crosstalk of hypoxia and inflammatory pathways was observed.
    Conclusion: These dissimilar responses of breast cancer cell lines suggest that therapy efficiency with anti-VEGF, anti-IL-1β, or curcumin will also vary within breast cancers.
    Keywords:  Breast cancer; ERK; VEGF; curcumin; interleukin-1β; p38-MAPK
    DOI:  https://doi.org/10.32604/or.2025.072793
  6. Int J Cancer. 2026 Mar 07.
    Reprogramming innate immunity to overcome endocrine resistance in estrogen receptor-positive breast cancer.
    Siti Nur Hasyila Muhammad, Maryam Azlan, Agustine Nengsih Fauzi.
      Estrogen receptor-positive (ER+) breast cancer accounts for the majority of breast cancer cases worldwide, yet the long-term efficacy of endocrine therapy is limited by resistance and recurrence. While tumor-intrinsic mechanisms of endocrine resistance are well established, growing evidence highlights the contributions of innate immune cells and the tumor microenvironment (TME) in shaping therapeutic outcomes. This review synthesizes recent advances into how tumor-associated macrophages (TAMs), natural killer (NK) cells, myeloid-derived suppressor cells (MDSCs), and tumor-associated neutrophils (TANs) collectively foster an immunosuppressive TME that undermines endocrine responsiveness. Central to this crosstalk is the STAT3 signaling pathway, which integrates inflammatory and metabolic stress signals to drive immune reprogramming, promotes tumor progression, and facilitates therapy resistance. By activating tolerogenic pathways and inhibiting anti-tumor immunity, STAT3 provides a mechanistic link between innate immune dysregulation and endocrine resistance. Preclinical studies demonstrate that STAT3 inhibition can restore tamoxifen sensitivity in resistant ER+ breast cancer models, highlighting its therapeutic potential. These insights reveal the immunological complexity of endocrine resistance and provide rationale for combinatorial strategies integrating endocrine therapy with immunomodulation. Future approaches that incorporate STAT3 inhibitor, immune checkpoint blockade, and biomarker-guided patient selection may transform the management of ER+ breast cancer, offering more durable and clinically meaningful outcomes by acknowledging the emerging interactions between immune dysregulation and metabolic stress in resistant ER+ breast cancer.
    Keywords:  ER‐positive breast cancer; endocrine resistance; innate immunity; natural killer cells; tumor‐associated macrophages
    DOI:  https://doi.org/10.1002/ijc.70421
  7. PNAS Nexus. 2026 Mar;5(3): pgag027
    In vivo imaging of metabolic heterogeneity across three endpoints relevant to aggressive breast cancer.
    Victoria W D'Agostino, Michelle Kwan, Adelle Yong, Kira Grossman, Enakshi D Sunassee, Megan C Madonna, Matthew Hirschey, Gregory M Palmer, Nirmala Ramanujam.
      Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor prognosis and a high likelihood of recurrence. Residual disease after therapy is a key predictor of recurrence, often driven by intratumoral metabolic heterogeneity. Accumulating evidence indicates that tumors are able to shift between glycolysis and oxidative metabolism and alter nutrient preferences to sustain growth and resist therapy. We have developed a in vivo microscope that enables near-simultaneous measurements of fluorescent metabolic surrogates of glucose, fatty acids, and oxidative phosphorylation through a combination of spectral separation and sequential delivery schemes. Widefield imaging with uniform illumination across the entire tumor landscape (5 mm × 5 mm) informs on the spatial distribution of these metabolic probes. We used this technology to investigate metabolic heterogeneity of a murine model of TNBC (4T1 tumor line) and normal mammary tissues that have distinctly different metabolic pathways. Mammary tissues relied primarily on oxidative metabolism and showed high levels of glucose and fatty acid uptake across the entire imaging area reflecting a single metabolic phenotype. Though tumors were predominantly glycolytic, they displayed a heterogeneous distribution of nutrient preferences with regions dominated by either fatty acid uptake, glucose uptake, or both. Taken together, this work highlights the importance of not only capturing multiple metabolic endpoints but also investigating their spatial relationships to understand heterogeneity in key substrates and metabolic pathways for energy production in vivo.
    Keywords:  breast cancer; fatty acid oxidation; fluorescence microscopy; glycolysis; tumor metabolism
    DOI:  https://doi.org/10.1093/pnasnexus/pgag027
  8. Br J Haematol. 2026 Mar 14.
    An oncogenic, truncated FGFR1 variant cooperates with SPFQ/NONO to regulate gene transcription in FGFR1-driven leukaemia.
    John K Cowell, Xuexiu Fang, Stephanie F Mori, Tianxiang Hu.
      A truncated derivative of Fibroblast growth factor receptor-1 (FGFR1) (tnFGFR1) independently transforms haematopoietic stem cells leading to a stem cell-like leukaemia/lymphoma syndrome (SCLL). In mouse models, these transformed cells show extensive genetic reprogramming that is distinct from cells transformed with full-length chimeric FGFR1 kinases. We now show that the truncated derivative is insensitive to kinase inhibitors, and its increased expression is related to resistance to kinase inhibitors. Chromatin immunoprecipitation (ChIP) analysis shows that tnFGFR1 can occupy the promoters of the Myc, Flt3 and Kit genes suggesting a transcription regulatory function. However, without a deoxyribonucleic acid-binding motif, tnFGFR1 must interact with binding partners that supply this function. To define this potential regulatory complex, we performed immunoprecipitation-mass spectroscopy (IP-MS) and demonstrate that tnFGFR1 is present in a complex with the splicing factor proline- and glutamine-rich (SFPQ) protein and non-POU domain-containing octamer-binding protein (NONO) protein. In addition, this protein complex is present on the promoters of target genes Flt3 and Kit, and knockdown of either SFPQ or NONO prevents activation of their target genes. In addition, treatment with the NONO inhibitor auranofin suppresses cell proliferation of tnFGFR1-transformed cells in vitro mitigating leukaemia progression in vivo in a mouse model. Thus, future targeting of this tnFGFR1 transcription complex may provide a means for treating tnFGFR1-driven leukaemia.
    Keywords:  FGFR1; NONO; SFPQ; leukaemia; resistance
    DOI:  https://doi.org/10.1111/bjh.70426
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