bims-merabr 2025-12-21 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2025–12–21
seven papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

Palmitic acid fuels triple-negative breast cancer through metadherin-dependent fatty acid β-oxidation: Relevance to high fat diet-induced breast cancer progression.
ST6GAL1 Promotes Epithelial-to-Mesenchymal Transition in Breast Cancer via the HIF-HK2 Signaling Pathway.
Single-cell RNA-seq reveals breast cancer heterogeneity and identifies TCP1 as a therapeutic target in breast cancer.
Lactate mitochondrial oxidation drives stemness potential in metastatic breast cancer.
MAP3K1/MAP2K4 mutations drive breast cancer progression by compensating for TP53 loss through inactivation of the JNK2-p53-FOSL1 axis.
Notch1 regulates Orai1 and Orai3 expression in breast cancer cells.
Breast cancer-derived exosomal miR-92a-3p stimulates malignant progression by driving TLR4/NF-κB-mediated macrophage M2 polarization.

Cell Signal. 2025 Dec 12. pii: S0898-6568(25)00735-1. [Epub ahead of print]139 112320

Palmitic acid fuels triple-negative breast cancer through metadherin-dependent fatty acid β-oxidation: Relevance to high fat diet-induced breast cancer progression.

Sunita Kumari, Shashikanta Sahoo, Sriravali Pulipaka, Annatta Thomas, Madhusudana Kuncha, Srigiridhar Kotamraju.

  Diets rich in saturated fats, specifically palmitic acid (PA), are associated with increased breast cancer risk. However, the exact mechanisms linking dietary fat and cancer progression remain unclear. Herein, we show that PA increases the levels of metadherin (MTDH), an oncogene, and its spliced isoform MTDHΔ7 in triple-negative breast cancer (TNBC) cells. PA significantly increased TNBC cell proliferation and invasiveness in an MTDH-Wt/Δ7-dependent way. Intriguingly, while PA alone promoted mitochondrial fatty acid β-oxidation (FAO), the addition of PA to TNBC cells stably expressing MTDH-Wt/MTDHΔ7 further potentiated FAO and ATP production. Conversely, PA failed to increase FAO in TNBC cells stably depleted of MTDH-Wt/MTDHΔ7. Also, etomoxir, a carnitine palmitoyl transferase (CPT)1 inhibitor, decreased PA- and MTDH-Wt/Δ7-induced TNBC cell invasive potential. Mechanistically, MTDH-Wt/MTDHΔ7-mediated increase in SIRT3 activity led to the activation of CPT1 via its deacetylation, promoting FAO and raising acetyl-CoA levels. Moreover, overexpression of MTDH-Wt/MTDHΔ7 notably increased free fatty acids uptake and subsequent consumption by boosting CD36 levels. Accordingly, depletion of either SIRT3 or CD36 significantly abrogated MTDH-Wt/MTDHΔ7-induced fatty acids uptake and subsequent FAO. Thus, MTDH-Wt/MTDHΔ7 plays a crucial role in utilizing fatty acids to fuel mitochondrial metabolism in TNBC cells. Further, SCID mice bearing sh.MTDH-Wt or sh.MTDHΔ7-MDA-MB-231cells fed a high-fat diet (HFD) showed significant resistance to tumor growth and metastatic spread compared to mice bearing parental MDA-MB-231 cells fed either HFD or chow diet. In conclusion, this study highlights a novel mechanism by which PA or HFD can promote TNBC aggressiveness through MTDH-mediated upregulation of mitochondrial FAO.

Keywords:  Breast cancer; FAO; HFD; MTDH; Palmitic acid

DOI:  https://doi.org/10.1016/j.cellsig.2025.112320
Breast Cancer (Dove Med Press). 2025 ;17 1199-1211

ST6GAL1 Promotes Epithelial-to-Mesenchymal Transition in Breast Cancer via the HIF-HK2 Signaling Pathway.

Dongliang Ren, Dengfeng Xue, Zhichao Hou, Huijuan Xu, Xinzheng Li.

   Background and Purpose: Breast cancer presents a substantial clinical challenge because of its complex aetiology and diverse phenotypic presentations. ST6Gal1 expression and epithelial-to-mesenchymal transition (EMT) frequently lead to metastasis, drug resistance and poor prognosis in many cancers. Nevertheless, the molecular details surrounding ST6GAL1 in the carcinogenesis of breast cancer, especially in the EMT of breast cancer, remain unclear. The objective of this study was to clarify the possible role and mechanism of ST6GAL1 in breast cancer.
Methods: PCR, WB, and IHC were employed to analyze the expression of ST6GAL1, epithelial-mesenchymal transition (EMT) markers, and components of the HIF-HK2 signaling pathway in MCF-10A, MDA-MB-231, and MCF-7 cells. Wound-healing, cell adhesion, drug resistance and extracellular matrix invasion assays were used to analyse the effects of ST6GAL1 on the biological process of breast cancer cells. The HIF-HK2 signalling pathway was also analysed.
Results: ST6GAL1 expression is increased in breast cancer. Altered expression of ST6GAL1 affects the biological function of breast cancer cells both in vitro and in vivo. ST6GAL1 knockdown inhibited EMT in breast cancer cells. ST6GAL1 Mediates the Activity of the HIF-HK2 Signalling Pathway in Breast Carcinoma Cells.
Conclusion: In our study, in vitro and in vivo models revealed that ST6GAL1 promotes malignant phenotypes in breast cancer cells and regulates the EMT process through activation of the HIF-HK2 signalling pathway.

Keywords:  EMT; HIF-HK2 signalling pathway; ST6GAL1; breast cancer

DOI:  https://doi.org/10.2147/BCTT.S555609
PeerJ. 2025 ;13 e20451

Single-cell RNA-seq reveals breast cancer heterogeneity and identifies TCP1 as a therapeutic target in breast cancer.

Houman Wu, Haiyang Du, Gao Si, Xuejie Song, Fuchun Si.

  Breast cancer is composed of diverse cell populations, and this intratumoral heterogeneity profoundly affects clinical behavior. Here, we leveraged single cell RNA sequencing (scRNA-seq) of 68 breast cancer specimens to dissect tumor heterogeneity at high resolution. Unsupervised clustering identified all major cell types of the tumor microenvironment (TME)-including malignant epithelial cells, fibroblasts, T cells, macrophages, endothelial cells, and others-with striking variability in their proportions across molecular subtypes. For example, a BRCA1-mutant triple-negative breast cancer (TNBC) sample showed dense immune infiltration, whereas an estrogen receptor (ER)-positive tumor was mostly epithelial, consistent with known subtype differences in immunogenicity. We applied inference of copy number variations (inferCNV) to distinguish malignant epithelial cells, identifying ~90,000 tumor cells with significant copy-number aberrations enriched for cancer hallmark pathways. Re-clustering of these malignant cells revealed five discrete subpopulations. Notably, a KRT17-positive subcluster displayed the highest stemness score and a distinctive ETS-family transcription factor (ERG) regulon, suggesting a stem-like phenotype. Using The Cancer Genome Atlas (TCGA) cohort, we found that genes upregulated in this KRT17+ subpopulation, particularly NFKBIA, PDLIM4, and TCP1 stratified patient survival. An 8-gene risk signature derived from the KRT17 program segregated patients into high- and low-risk groups with markedly different outcomes. High-risk tumors were characterized by an immunosuppressive TME enriched in M2-like macrophages, whereas low-risk tumors more often harbored lymphocyte-predominant infiltrates. Focusing on TCP1, a chaperonin subunit upregulated in high-risk tumors, we demonstrate that TCP1 knockdown in breast cancer cell lines substantially impairs cell migration (~50% reduction in wound closure) and invasion (P < 0.01). These findings reveal functionally distinct malignant cell states within breast cancer and identify TCP1 as a promising therapeutic target to disrupt aggressive, stem-like tumor cell programs, ultimately guiding more personalized treatment strategies.

Keywords:  Breast cancer; Heterogeneity; Single-cell RNA-seq; TCP1

DOI:  https://doi.org/10.7717/peerj.20451
Nat Commun. 2025 Dec 18.

Lactate mitochondrial oxidation drives stemness potential in metastatic breast cancer.

Jia-Jia Zhang, Ruo-Fei Tian, Chang-Geng Song, Rui Liu, Duo He, Gai-Qin Zhang, Xin-Yu Fan, Zi-Chuan Duan, Kun Zhang, Tian-Jiao Zhang, Ya-Tong Chen, Jian Zhang, Ke Wang, Ju-Mei Zhao, Xiang-Min Yang, Zhi-Nan Chen, Ling Li.

Metastatic cancer cells, originating from cancer stem cells with metastatic capacity, utilize nutrient flexibility to navigate the challenges of the metastatic cascade. However, the nutrient required to maintain the stemness potentials of metastatic cancer cells remains unclear. Here, we reveal that metastatic breast cancer cells sustain stemness and initiate metastasis upon detachment by taking up and oxidizing lactate. In detached metastasizing breast cancer cells, lactate is incorporated into the tricarboxylic acid cycle, boosting oxidative phosphorylation, and promoting the stemness potentials via α-KG-DNMT3B-mediated SOX2 hypomethylation. Moreover, lactate is taken up and oxidized in mitochondria by the CD147/MCT1/LDHB complex, which correlates with stemness potentials and tumor metastasis in patients with breast cancer. An intracellularly expressed single-chain variable fragment targeting mitochondrial CD147 (mito-CD147 scFv) effectively disrupts the mitochondrial CD147/MCT1/LDHB complex, inhibits lactate-induced stemness potential, depletes circulating breast cancer cells, and reduces metastatic burden, suggesting promising clinical applications in reducing lactate-fueled metastasis.

DOI: https://doi.org/10.1038/s41467-025-67091-y
Breast Cancer Res. 2025 Dec 16.

MAP3K1/MAP2K4 mutations drive breast cancer progression by compensating for TP53 loss through inactivation of the JNK2-p53-FOSL1 axis.

Sike Hu, Ailing Ji, Manxue Wang, Xia Li, Lili Sun, Ruifang Gao, Ying Zhang.

   BACKGROUND: Cancer progression is driven by somatic mutations, with alterations in driver genes such as tumor suppressors and oncogenes playing critical roles. In breast cancer (BRCA), mutations in MAP3K1 and MAP2K4 are recurrent, especially in estrogen receptor-positive (ER+) subtypes, yet their functional significance and mechanistic contributions remain incompletely understood. This study aims to elucidate the role of MAP3K1/MAP2K4 mutations in BRCA pathogenesis.
METHODS: We performed integrated genomic analyses using data from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohorts. Functional validation was conducted in breast cancer cell lines (e.g., MCF-7, ZR-75-1) using shRNA-mediated knockdown, overexpression of dominant-negative MKK4 (MKK4DN), and western blotting. In vivo tumor growth and metastasis were assessed using a xenograft mouse model. Proteomic and phosphoproteomic data from Clinical Proteomic Tumor Analysis Consortium (CPTAC) were analyzed to evaluate JNK pathway activity and FOSL1 expression across multiple cancer types.
RESULTS: MAP3K1 and MAP2K4 were identified as frequently mutated in BRCA, with mutation spectra dominated by loss-of-function alterations. These mutations exhibited mutual exclusivity with TP53 alterations and were enriched in ER + tumors. Mechanistically, MAP3K1/MAP2K4 loss led to reduced JNK2 phosphorylation, impaired p53 activation at Ser15, and subsequent upregulation of FOSL1 (encoding FRA1), promoting tumor proliferation and metastasis. In vivo, MKK4DN (dominant-negative MAP2K4) expression enhanced tumor growth and lung metastasis, accompanied by decreased phospho-JNK/p53 and increased FRA1. Pan-cancer analysis revealed that MAP3K1/MAP2K4 mutations compensate for TP53 loss in regulating FOSL1 expression, particularly in tumors with moderate TP53 mutation rates.
CONCLUSIONS: Our findings establish MAP3K1 and MAP2K4 as key tumor suppressors in BRCA that operate via the JNK2-p53-FOSL1 axis. Their inactivation provides an alternative mechanism for p53 pathway disruption, adhering to the "minimal necessary alteration" principle in cancer signaling. This study highlights the dual regulatory mechanisms controlling FRA1 expression and offers insights into breast cancer heterogeneity, with potential implications for targeted therapy and patient stratification.

Keywords:  Breast cancer; Driver mutations; FRA1/FOSL1; JNK2; MAP2K4; MAP3K1; Metastasis; Mutual exclusivity; p53

DOI:  https://doi.org/10.1186/s13058-025-02195-3
Sci Rep. 2025 Dec 18.

Notch1 regulates Orai1 and Orai3 expression in breast cancer cells.

Joel Nieto-Felipe, Alvaro Macias-Diaz, Sandra Alvarado, Pedro C Redondo, Vanesa Jimenez-Velarde, Jose J Lopez, Astrid Gorischek, Isaac Jardin, Tarik Smani, Juan A Rosado.

  Store-operated Ca²⁺ entry (SOCE) is a major pathway for Ca²⁺ entry that regulates several cellular functions. SOCE remodeling mediated by changes in the expression and/or function of the Orai channels results in the reorganization of intracellular Ca2+ homeostasis leading to a variety of pathologies, including cancer. Notably, a significant alteration of Orai function has been reported in breast cancer cells, where the dysregulation of the Notch1 signaling pathway plays a role in the development and progression of cancer hallmarks. Here, we have investigated the possible role of Notch1 in the regulation of the expression of Orai1 and Orai3 in different breast cancer cell lines. Expression of the active form of Notch1, as well as cell stimulation with the Notch1 agonist Jagged-1 (Jag-1), demonstrates a differential role of Notch1 in the regulation of Orai expression in non-tumoral breast epithelial cells and triple negative or luminal breast cancer cells. The role of Notch1 was confirmed using DAPT, a γ-secretase inhibitor that prevents activation of the Notch pathway. Modulation of Orai1 and Orai3 expression by Notch1 was paralleled by changes in SOCE. The effect in Orai expression mediated by activation of Notch1 signaling pathway was mimicked by the expression of HEY1 or the non-phosphorylatable HEY1-S68A mutant; by contrast, expression of the phosphomimetic HEY1-S68D mutant was without effect on Orai expression. Understanding the Notch1-HEY1-Orai axis might provide insights into the development of subtype-specific therapeutic strategies targeting breast cancer.

Keywords:  Notch1; Orai1; Orai3; Store-operated Ca2+ entry

DOI:  https://doi.org/10.1038/s41598-025-33071-x
Biochem Biophys Res Commun. 2025 Dec 11. pii: S0006-291X(25)01840-6. [Epub ahead of print]795 153124

Breast cancer-derived exosomal miR-92a-3p stimulates malignant progression by driving TLR4/NF-κB-mediated macrophage M2 polarization.

Sheng Ding, Jian Wang, Jing Pei.

  Breast cancer (BC) cell-derived exosomes significantly reshape the tumor microenvironment; however, the key mechanisms driving tumor progression remain unclear. This study employed transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blotting to analyze exosomes from MCF-10A normal breast epithelial cells and MDA-MB-231/MCF-7 breast cancer cells. Treatment of parental BC cells with tumor-derived exosomes markedly enhanced malignant characteristics, whereas exosomes from miR-92a-3p-knockdown cells reversed these malignant phenotypes. Bioinformatics analysis of the EVMiRNA database initially identified miR-92a-3p as the most prominently upregulated miRNA in blood exosomes from BC patients. This finding was validated by qRT-PCR, which demonstrated significant overexpression of miR-92a-3p in tumor-derived exosomes. Exosomal miR-92a-3p induced immunosuppressive M2 polarization of THP-1-derived macrophages, evidenced by upregulated mRNA levels of Arg-1, Ym1, and IL-10, an increased proportion of CD206+cells; and elevated IL-10 secretion accompanied by reduced TNF-α secretion. Mechanistically, the TLR4/NF-κB pathway in macrophages was activated by parental exosomes, resulting in increased expression of TLR4 and phosphorylated p65, whereas miR-92a-3p-knockdown exosomes inhibited this pathway activation. Importantly, we confirmed that miR-92a-3p directly targets the 3'untranslated region (3'UTR) of TLR4 using a luciferase reporter assay. In conclusion, tumor-derived exosomal miR-92a-3p exerts dual effects: it directly enhances the invasiveness of BC cells and promotes M2 polarization by activating the TLR4/NF-κB axis in macrophages, thereby accelerating tumor progression. These findings highlight the pivotal role of miR-92a-3p in tumor-exosome crosstalk and identify it as a promising therapeutic target for BC.

Keywords:  Breast cancer; Exosomes; M2 macrophage polarization; TLR4/NF-κB pathway; miR-92a-3p

DOI:  https://doi.org/10.1016/j.bbrc.2025.153124