bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2025–09–14
six papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. CHDH Promotes Breast Cancer Metastasis Relying on IL17RB/CREB1 Signalling Activation.
  2. β-Hydroxybutyrate promotes chemoresistance and proliferation in breast cancer cells.
  3. EPHA2 promotes triple-negative breast cancer progression by suppressing pyroptosis via the AKT/PI3K/mTOR pathway.
  4. ERK3/MAPK6 promotes triple-negative breast cancer progression through collective migration and EMT plasticity.
  5. Molecular Mechanisms of Estrogens in the Induction of Epithelial-to-Mesenchymal Transition and Metastasis in Breast Cancer.
  6. AID/HAT1-mediated epigenetic priming of JAG1/NOTCH signaling drives tumor microenvironment reprogramming in TNBC.
  1. J Cell Mol Med. 2025 Sep;29(17): e70792
    CHDH Promotes Breast Cancer Metastasis Relying on IL17RB/CREB1 Signalling Activation.
    Yifei Li, Yipeng Liu, Xiaowen Yang, Xinzhuang Shen, Zongjun Liu, Yuqiu Ma, Yiting Zhan, Xinyu Jiang, Chengjin Liang, Xiaoyuan Zhang, Huan Liu, Wenzhi Shen.
      The involvement of Choline Dehydrogenase (CHDH) in metabolic disorders and tumour progression has garnered significant scholarly interest. However, the specific role of CHDH in the metastasis and progression of breast cancer (BC) has been less thoroughly investigated. Our research indicates that CHDH protein expression is markedly elevated in breast cancer tissues compared to normal tissues, and this expression is positively correlated with the tumour node metastasis (TNM) stage of breast cancer. Furthermore, CHDH levels were found to be significantly higher in breast cancer cell lines relative to normal breast cells. The silencing of CHDH expression resulted in a reduction of breast cancer cell migration, while the overexpression of CHDH facilitated increased migration and tumour metastasis in vivo. Investigations into the underlying mechanisms revealed that CHDH influences the expression of IL17RB and activates Cyclic-AMP Response Element-Binding Protein (CREB), thereby mediating breast cancer metastasis. The application of an IL17RB antibody and the CREB inhibitor 666-15 effectively abolished CHDH-mediated migration of breast cancer cells in vitro. These findings suggest that CHDH plays a critical role in promoting breast cancer metastasis, potentially offering new targets and strategies for the treatment of metastatic breast cancer.
    Keywords:  CHDH; IL17RB/CREB; breast cancer (BC); metastasis; migration
    DOI:  https://doi.org/10.1111/jcmm.70792
  2. Biochem Biophys Rep. 2025 Dec;44 102217
    β-Hydroxybutyrate promotes chemoresistance and proliferation in breast cancer cells.
    Milad Mashinchian, Somayeh Vandghanooni, Amir Reza Karamibonari, Morteza Eskandani.
      Breast cancer is the most prevalent cancer among women, posing significant challenges due to its heterogeneity. Recent studies suggest that the ketogenic diet (KD) may enhance chemotherapy efficacy by modulating cancer cell metabolism, particularly through the elevation of ketone bodies like β-hydroxybutyrate (BHB). This study investigates the effects of BHB on breast cancer cells using both 2D and 3D culture models, focusing on its role in developing resistance to fluorouracil (5-FU). We utilized CF41.Mg canine mammary gland cancer cells and MCF7 human breast cancer cells to assess BHB's effects as a pre-treatment and post-treatment under varying glucose conditions. The findings indicated that BHB notably increased cell viability, proliferation, and migration. Pre-treatment resulted in a 52.94 % increase in viability for CF41.Mg cells and a 54.73 % increase for MCF7 cells after 48 h, compared to treatment with 5-FU alone. This enhancement persisted at 72 h, indicating BHB's potential to promote resistance to 5-FU. In 3D spheroid models, which better mimic the tumor microenvironment, BHB pre-treatment significantly increased spheroid size and conferred resistance to 5-FU in both cell lines. Additionally, BHB pre-treatment elevated the expression of proliferation markers such as Ki-67 and tumorigenic markers like MUC-1 (Mucin 1), while showing no significant impact on mesenchymal markers like N-cadherin and vimentin. These findings suggest that BHB significantly increases resistance to 5-FU, indicating that BHB may enable cancer cells to evade chemotherapy-induced stress. Our findings raise important questions about the potential dual role of BHB and KD in promoting cancer cell survival while potentially complicating treatment outcomes.
    Keywords:  Breast cancer; Fluorouracil; Ketogenic diet; Tumorigenesis; β-Hydroxybutyric acid
    DOI:  https://doi.org/10.1016/j.bbrep.2025.102217
  3. Front Oncol. 2025 ;15 1620122
    EPHA2 promotes triple-negative breast cancer progression by suppressing pyroptosis via the AKT/PI3K/mTOR pathway.
    Xiaoying Huang, Li Na, Qingkai Han, Qilun Liu, Ligang Wu.
       Background: Breast cancer (BRCA) is the most prevalent cancer in women, with triple-negative breast cancer (TNBC) accounting for 15-20% of cases. TNBC is associated with higher rates of metastasis, recurrence, and poorer prognosis, underscoring the urgent need for new diagnostic and therapeutic strategies.
    Methods: In this study, multiple public online platform, including UCSC Genome, UALCAN, Kaplan Meier plotter, DepMap and Single Cell Portal were used to detect the expression of EPHA2 in TNBC. Cell Counting Kit-8 (CCK-8) and transwell assays were conducted to assess proliferation and invasion. KOBAS bioinformatics, transmission electron microscopy (TEM), ELISA, western blot and quantitative real-time PCR experiments were employed to detect the association and effects of EPHA2 on pyroptosis in BRCA.
    Results: EPHA2 was highly expressed in TNBC, and showed a negative correlation with survival. Single-cell analysis indicated that EPHA2 was mainly expressed in stromal and epithelial cells, particularly within TNBC compartments. Furthermore, we found that EPHA2 knockdown inhibited cell proliferation and invasion, and induced pyroptosis, as evidenced by increased level of pyroptosis-related protein (IL-18, IL-1β) and characteristic morphological changes. Moreover, a relationship between EPHA2, pyroptosis, and the AKT/PI3K pathway was established and confirmed. Additionally, we observed a decreased expression of ferroptosis-associated marker named SLC7A11, suggesting that this transporter may mediate the effects of AKT inhibition on pyroptosis.
    Conclusions: In summary, our findings illuminated the dual roles of EPHA2 in TNBC, influencing both tumor progression and cell death pathways. We hypothesize that SLC7A11 serves as a key regulator of pyroptosis in the context of EPHA2 and AKT/PI3K signaling. These insights underscore the potential of targeting these pathways in developing therapeutic strategies for BRCA treatment. Further investigations into the mechanisms underlying SLC7A11's roles could enhance our understanding of its therapeutic implications.
    Keywords:  AKT/PI3K; EPHA2; SLC7A11; pyroptosis; triple-negative breast cancer
    DOI:  https://doi.org/10.3389/fonc.2025.1620122
  4. Front Oncol. 2025 ;15 1563969
    ERK3/MAPK6 promotes triple-negative breast cancer progression through collective migration and EMT plasticity.
    Sofia Morazzo, Soraia Fernandes, Marina Fortea, Helena Skálová, Daniel Pereira-Sousa, Marco Cassani, Kamila Vrzalová, Filip Kafka, Jan Vrbský, Mathilde Soulez, Sylvain Meloche, Ole Morten-Seternes, Veronika Bosáková, Jaeyoung Shin, Jan Frič, Kristina Haase, Giancarlo Forte.
      Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, in which epithelial-to-mesenchymal transition (EMT) plasticity is required for successful metastasis. ERK3 has been implicated in promoting breast cancer migration and invasion, but the mechanisms remain elusive. Here, we investigated ERK3 expression across patient-derived datasets and explored its role in promoting EMT plasticity using different 2D and 3D in vitro models to investigate cell-extracellular matrix adhesion, migration and invasion, anchorage-independent growth, extravasation and colonization. We have established an association between ERK3 overexpression and aggressive breast cancer phenotypes, higher tumour plasticity, as informed by its grade, and poor clinical outcomes. Based on the hypothesis that ERK3 contributes to TNBC progression by supporting a partial-EMT state, we showed that ERK3 contributes to different steps of the metastatic process, especially by enabling collective migration but also by modulating other functional aspects related to an active EMT program. In conclusion, our results demonstrate that ERK3 contributes to TNBC progression and potentially metastasis by promoting EMT plasticity and collective migration.
    Keywords:  Extracellular signal-regulated kinase 3 (ERK3); Triple-negative breast cancer (TNBC); collective migration; epithelial-mesenchymal plasticity (EMP); epithelial-to-mesenchymal transition (EMT); mitogen-activated protein kinase 6 (MAPK6)
    DOI:  https://doi.org/10.3389/fonc.2025.1563969
  5. Int J Mol Sci. 2025 Sep 04. pii: 8589. [Epub ahead of print]26(17):
    Molecular Mechanisms of Estrogens in the Induction of Epithelial-to-Mesenchymal Transition and Metastasis in Breast Cancer.
    Javier Jiménez-Salazar, Luis Garcia-Melo, Nikola Batina, Adriana Alarcón-Aguilar, Armando Luna-López, Paulina Hernández-Garcés, Rebeca Damián-Ferrara, Pablo Damián-Matsumura.
      Estrogens have been widely shown to induce cell proliferation in breast cancer (BC) cells. Recently, we have described their involvement in the induction of epithelial-mesenchymal transition (EMT), migration, and invasion. The aim of this work is to review the molecular mechanisms by which estradiol (E2) activates different signaling pathways, both genomic and non-genomic, through binding to different estrogen receptors (ERs), depending on the phosphorylated amino acid (Ser-118 or Tyr-537). The relevance of the present work lies in the molecular details of c-Src kinase activation by the membrane estrogen receptor (mER) and its effects on the early and late phases of EMT. This process initiates a loss of cell adhesion, leading to migration, which culminates in metastasis of cancer cells to distant tissues. Understanding how estrogens induce metastasis will facilitate the development of better strategies to counteract the lethality of BC. Finally, the quantification of Snail may serve as a molecular marker in the early stages of tumor progression, as well as the use of drugs against c-Src and ERs, as they may be therapeutic targets.
    Keywords:  Src family kinases; cell adhesion; cell migration; estrogen receptors; signal transduction
    DOI:  https://doi.org/10.3390/ijms26178589
  6. Cell Signal. 2025 Sep 08. pii: S0898-6568(25)00533-9. [Epub ahead of print]136 112118
    AID/HAT1-mediated epigenetic priming of JAG1/NOTCH signaling drives tumor microenvironment reprogramming in TNBC.
    Junna Jiao, Zhuangwei Lv, Kai Zhang, Ruihan Wang, Xiaoyu Shi, Lulu Liu, Junyue Jiao, Yi'ang Niu, Liwei Guo.
      Triple-negative breast cancer (TNBC) presents a formidable therapeutic challenge due to its aggressive behavior, molecular heterogeneity, and lack of actionable targets. This study identifies activation-induced cytidine deaminase (AID) as a pivotal epigenetic driver reprogramming the tumor microenvironment (TME) via non-canonical regulation of NOTCH signaling. Mechanistically, AID recruits histone acetyltransferase 1 (HAT1) to form a chromatin-remodeling complex that binds the JAG1 promoter region (-1.5 kb to -1.1 kb), inducing H4K5 acetylation and transcriptional activation. This AID/HAT1-JAG1 axis amplifies NOTCH signaling in TNBC models, and genetic ablation of either AID or JAG1 suppresses malignant progression. Pharmacological disruption using 4-Deoxyuricine (AID antagonist) and MG149 (HAT1 inhibitor) reduces JAG1 acetylation, attenuates NOTCH signaling, and reshapes the TME by depleting AID/HAT1-JAG1 axis and enhancing the infiltration of T cells, NK cells, and B cells. Clinically, AID and JAG1 co-expression enhances immune cell infiltration in TME, which predicts poor survival in TNBC cohorts. Our findings redefine AID's role beyond its function in mediating mutagenesis, positioning it as a master epigenetic regulator of TNBC plasticity through acetylation-dependent NOTCH activation. These results resolve the paradox of NOTCH inhibitor resistance by identifying JAG1's epigenetic priming as a prerequisite for ligand-receptor signaling. Targeting the AID/HAT1-JAG1 axis offers a dual therapeutic strategy to overcome TME-mediated therapy resistance and provides a blueprint for precision immunotherapy in AID-positive TNBC subgroups.
    Keywords:  Activation induced-cytidine deaminase; Epigenetic modification; Histone acetyltransferase 1; NOTCH signal; Triple negative breast cancer; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112118
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