bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2025–05–25
seven papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. Rewired glycolysis by DTL accelerates oncometabolite L-lactate generation to promote breast cancer progression.
  2. KIF20A promotes triple-negative breast cancer progression via activation of the IL-17 signaling pathway.
  3. Cytoplasmic HMGB1 promotes the activation of JAK2-STAT3 signaling and PD-L1 expression in breast cancer.
  4. Downregulation of PIP4K2C inhibits the breast cancer cell proliferation, migration and invasion.
  5. Extracellular cell matrix stiffness-driven drug resistance of breast cancer cells via EGFR activation.
  6. EMT induction in normal breast epithelial cells by COX2-expressing fibroblasts.
  7. NCAPD3 contributes to lung cancer progression through modulated lactate-induced histone lactylation and MEK/ERK/LDHA axis.
  1. Front Oncol. 2025 ;15 1583752
    Rewired glycolysis by DTL accelerates oncometabolite L-lactate generation to promote breast cancer progression.
    Yuhao Liu, Jinting Li, Yiren Cao, Mengzhu Lv.
      Breast cancer (BC) has become the leading cause of global cancer incidence. Despite therapeutic advances, a critical unmet need persists for identifying novel therapeutic targets. Our integrated bioinformatics analysis identified DTL, a component of the Cullin-RING ligase (CRL) E3 ubiquitin ligase family, as significantly upregulated in BC tissues. This upregulation correlated with poor patient prognosis, cancer stemness, and metabolic reprogramming, which was driven by genetic alterations such as gene amplification and reduced promoter methylation. Functional studies demonstrated that DTL promoted breast cancer cell proliferation and migration in vitro through glycolysis remodeling. Mechanistically, DTL positively regulated key glycolytic enzymes (HK2, ENO1, PKM2, and LDHA) independently of its canonical ubiquitin ligase activity and directly interacted with LDHA. Notably, exogenous L-lactate directly enhanced BC tumor growth and metastasis. Collectively, our findings reveal a non-canonical mechanism whereby DTL drives glycolysis to generate the oncometabolite L-lactate, which directly sustains breast cancer malignancy independent of protein degradation. The strong association between DTL upregulation and adverse clinical outcomes, coupled with its multifaceted regulatory roles in tumor biology, highlighting its therapeutic potential as a novel target in BC.
    Keywords:  DTL; L-lactate; breast cancer; glycolysis; progression
    DOI:  https://doi.org/10.3389/fonc.2025.1583752
  2. Biochem Biophys Res Commun. 2025 May 15. pii: S0006-291X(25)00745-4. [Epub ahead of print]770 152031
    KIF20A promotes triple-negative breast cancer progression via activation of the IL-17 signaling pathway.
    Zhiyong Wang, Dongning Shi, Xin Li, Xia Wang, Junwen Bai.
       BACKGROUND: Triple-negative breast cancer (TNBC), the only breast cancer subtype lacking effective targeted therapies, is associated with a poor prognosis. Emerging evidence highlights the oncogenic role of kinesin family member 20A (KIF20A) in human malignancies, though its mechanistic contributions to TNBC progression remain poorly understood.
    METHODS: Candidate target genes were screened via bioinformatic analysis. Following KIF20A knockdown, we utilized cell counting kit-8, 5-Ethynyl-2'-deoxyuridine staining, transwell, and wound healing assays to assess TNBC cell viability, proliferative capacity, migratory ability, and invasive potential of TNBC cells. In vivo, we measured the volume, weight, and proliferation of solid tumors. Moreover, the downstream pathway of KIF20A was screened by bioinformatic analysis and validated by an agonist and an inhibitor for the interleukin 17 (IL-17) pathway. The expression levels of proteins associated with the IL-17 pathway were assessed via Western blot.
    RESULTS: KIF20A, highly overexpressed in TNBC, was screened out as a promising target gene. In vitro, KIF20A knockdown significantly impaired TNBC cell viability, proliferation, migration, and invasion. In vivo, KIF20A knockdown suppressed the growth and proliferation of solid tumors in nude mice xenograft models. Mechanistically, the IL-17 signaling pathway was screened out and the expression of proteins in this pathway was suppressed by KIF20A knockdown. The agonist for the IL-17 signaling countered the impact of KIF20A knockdown on TNBC progression. Direct inhibition of IL-17 showed a similar effect as KIF20A silencing on TNBC cells.
    CONCLUSION: KIF20A downregulation suppresses TNBC progression via the inactivation of the IL-17 signaling pathway, suggesting KIF20A as a potential therapeutic target for TNBC.
    Keywords:  KIF20A; The IL-17 signaling pathway; Triple-negative breast cancer; bioinformatic analysis
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152031
  3. Mol Med. 2025 May 19. 31(1): 197
    Cytoplasmic HMGB1 promotes the activation of JAK2-STAT3 signaling and PD-L1 expression in breast cancer.
    Ju-Young Han, Woo Joong Rhee, Jeon-Soo Shin.
       BACKGROUND: High-mobility group box 1 (HMGB1) plays various roles depending on its subcellular localization. Extracellular HMGB1 interacts with receptors, such as toll-like receptor 4 and receptor for advanced glycation end products (RAGE), promoting cell proliferation, survival, and migration in cancer cells. It also increases the expression of programmed death-ligand 1 (PD-L1) in cancer cells by binding to RAGE. However, the effect of intracellular HMGB1 on the regulation of immune checkpoints such as PD-L1 has not been well characterized. In this study, we aimed to investigate the effects of intracellular HMGB1 on PD-L1 expression in breast cancer cells.
    METHODS: Human and mouse triple-negative breast cancer cells, MDA-MB-231 and 4T1, along with HMGB1-deficient mouse embryonic fibroblast cells, were cultured. HMGB1 overexpression was achieved using a Myc-tagged plasmid, while siHMGB1 constructs were used for gene silencing. Quantitative reverse-transcriptase PCR and western blot analysis were performed to assess gene and protein expressions. Confocal imaging, immunoprecipitation, and proximity ligation assays were used to investigate HMGB1 localization and Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) interactions. In vivo experiments were performed using tumor-bearing mice treated with STAT3 and HMGB1 inhibitors. Statistical analyses were performed using Student's t-tests, one-way analysis of variance, Pearson's correlation, and Kaplan-Meier survival analysis, with significance set at p < 0.05.
    RESULTS: In breast cancer cells, HMGB1 translocation from the nucleus to the cytoplasm increased the JAK2-STAT3 interaction and induced STAT3 phosphorylation, leading to increased STAT3 target signaling, including the epithelial-mesenchymal transition (EMT) phenotype and PD-L1 expression. Inhibition of nucleo-cytoplasmic translocation of HMGB1 decreased STAT3 phosphorylation and PD-L1 expression. Furthermore, HMGB1 enhanced breast cancer cell migration, invasion, and EMT, contributing to tumor growth in an in vivo mouse model that were mitigated by the HMGB1-targeted approach.
    CONCLUSIONS: These findings underscore the critical role of intracellular HMGB1 in modulating PD-L1 expression via the JAK2-STAT3 signaling pathways in breast cancer and suggest that targeting HMGB1 translocation is a promising strategy for breast cancer treatment.
    Keywords:  Breast cancer; HMGB1; JAK2; PD-L1; STAT3
    DOI:  https://doi.org/10.1186/s10020-025-01235-0
  4. Transl Oncol. 2025 May 19. pii: S1936-5233(25)00151-2. [Epub ahead of print]57 102420
    Downregulation of PIP4K2C inhibits the breast cancer cell proliferation, migration and invasion.
    Yue Jin, Jian Xue, Xinyue Li, Xiaoli Zhong.
      Phosphoinositide signaling pathway has garnered significant attention in recent years due to its implication in metabolic alterations associated with various human diseases, including breast cancer. Phosphatidylinositol-5-phosphate 4-kinase (PIP4K) catalyzes the phosphorylation of phosphatidylinositol-5-phosphate (PI5P) to produce phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2), a lipid that regulates signaling pathways associated with cancer cell growth and metastasis. In breast cancer, PIP4Ks, especially PIP4Kα and PIP4Kβ, have emerged as a significant player, with their dysregulation linked to tumor progression and poor prognosis. However, the role of PIP4Kγ (encoded by PIP4K2C), the other isoform of PIP4K family, remains largely uncharted in breast cancer. Here, we demonstrated that the expression of PIP4K2C is upregulated in breast cancer tissues opposed to the normal tissue utilizing the GTEx and the TCGA public database. The elevation of PIP4K2C expression is further confirmed in the breast cancer cell lines and tissues. Downregulated expression of PIP4K2C by siRNA lowered the subcellular PI(4,5)P2 and suppressed proliferation, migration and invasion of MDA-MB-468, MCF7 breast cancer cell lines. Our research substantiates PIP4K2C as a promising diagnostic and therapeutic biomarker for breast cancer, warranting further investigation into its mechanistic and clinical implications.
    Keywords:  Breast cancer; PI(4,5)P2; PIP4K2C; Phosphoinositide kinases
    DOI:  https://doi.org/10.1016/j.tranon.2025.102420
  5. Mechanobiol Med. 2023 Dec;1(2): 100023
    Extracellular cell matrix stiffness-driven drug resistance of breast cancer cells via EGFR activation.
    Tingting Li, Yichao Li, Hao Wu, Chong Peng, Jiawen Wang, Shihuan Chen, Tian Zhao, Shun Li, Xiang Qin, Yiyao Liu.
      Tumor progression is accompanied by complex structural changes in the extracellular matrix (ECM), which decrease the effective exposure of tumors to drugs. Breast cancer are highly heterogeneous with a typically high degree of ECM remodeling and stiffening. Therefore, it is especially important to explore the influence of ECM stiffness on breast cancer chemotherapy. Here, we fabricated 3D Methacrylate Gelatin (GelMA) hydrogels with varying stiffness by photo-crosslinking to simulate the change of tissue stiffness during the development of breast cancer. These 3D hydrogels were used to evaluate how MDA-MB-231 cells responded to the chemotherapy drug doxorubicin (DOX), the mechanical regulatory mechanism involved has also been investigated. The findings demonstrated that 15% GelMA hydrogel (9 ​kPa) increased the activity of EGFR to block the Hippo signaling pathway and activate Yes-associated protein (YAP). Activated YAP allowed cytosolic EGFR transport into the nucleus via binding with it, up-regulated the expression of their respective transcriptional targets, and thus generates drug resistance. Altogether, our study implicates that stiffness-dependent EGFR activation plays an important role in breast cancer drug resistance, indicating that targeting of both YAP and EGFR signals may present a promising therapeutic strategy for ECM stiffness-induced drug resistance.
    Keywords:  Breast cancer cells; Drug resistance; ECM stiffness; EGFR; YAP
    DOI:  https://doi.org/10.1016/j.mbm.2023.100023
  6. Cell Commun Signal. 2025 May 22. 23(1): 237
    EMT induction in normal breast epithelial cells by COX2-expressing fibroblasts.
    Minwoo Kang, Somayadineshraj Devarasou, Nam Ji Sung, Tae Yoon Kwon, Jennifer H Shin.
       BACKGROUND: The tumor microenvironment (TME) plays a pivotal role in cancer progression, with cancer-associated fibroblasts (CAFs) significantly influencing tumor behavior. Especially, elevated COX2 expressing fibroblasts within the TME, notably in collagen-dense tumors like breast cancer, has been recently emphasized in the literature. However, the specific effect of COX2-expressing CAFs (COX2+ CAFs) on neighboring cells and their consequent role in cancer progression is not fully elucidated.
    METHODS: We induced COX2+ fibroblasts by forcing the fibroblasts forming aggregates to undergo Nemosis as a proxy for COX2+ CAFs. This approach enabled us to simulate the paracrine interactions between COX2+ CAFs and normal breast epithelial cells via conditioned media from COX2+ fibroblasts. We developed an innovative in vitro platform that combines cell mechanics-based analysis and biomolecular assays to study the interactions between COX2+ fibroblasts and normal breast epithelial cells. By focusing on the mechanical characteristics of the cells and the epithelial-mesenchymal transition (EMT) marker expressions, we aimed to elucidate the paracrine mechanisms through which COX2+ CAFs influence the tumor microenvironment.
    RESULTS: Our in vitro findings demonstrate that COX2+ fibroblasts, through conditioned media, induce significant alterations in the mechanical behavior of normal breast epithelial cells, as evidenced by monolayer expansion measurements using traction force microscopy (TFM). This transition was further corroborated by single-cell morphology and motility analyses, as well as increased expression of mesenchymal markers, including SNAI1 at the mRNA level and vimentin at the protein level. EP4 inhibition partially reversed these changes, preserving cell-cell interactions, limiting monolayer expansion, and reducing mesenchymal-like features, suggesting that PGE2-EP4 signaling plays a key role in mediating the paracrine effects of COX2+ fibroblasts. Together, our findings support a model in which PGE2-EP4 signaling contributes to EMT induction, potentially involving SNAI1 regulation, with implications for targeting stromal-epithelial interactions in breast cancer.
    CONCLUSION: This study advances our understanding of the potential mechanisms by which COX2+ CAFs influence tumor progression within the breast tumor microenvironment (TME) through controlled in vitro investigations. By integrating cell mechanics-based analysis, biomolecular assays, and innovative in vitro cell-based modeling of COX2+ CAFs, we have delineated the contributory role of these cells in a controlled setting. These insights lay a groundwork for future studies that could explore the implications of these findings in vivo, potentially guiding targeted therapeutic strategies.
    Keywords:   COX2 ; Breast cancer; Cancer-associated fibroblasts; EMT; Fibroblasts; Nemosis; PGE2; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12964-025-02227-7
  7. Cancer Cell Int. 2025 May 23. 25(1): 189
    NCAPD3 contributes to lung cancer progression through modulated lactate-induced histone lactylation and MEK/ERK/LDHA axis.
    Zhibo Chang.
      Lung cancer (LC) is one of the most common malignant tumors globally. Non-SMC condensin II complex subunit D3 (NCAPD3) has been involved in the progression of many kinds of tumors. However, the effects of NCAPD3 in LC remain unclear. NCAPD3 expression was investigated by the Ualcan database and using Western blot. The effect of NCAPD3 on prognosis was explored via the Kaplan-Meier plotter database. Cell viability, colony formation, apoptosis, and Transwell assays, and in vivo tumorigenesis were performed to reveal the biological roles of NCAPD3. Glycolysis was assessed via measurement of glucose consumption, extracellular acidification rate (ECAR), lactate production, and ATP levels. The deeper mechanisms of NCAPD3 were investigated by Western blot and rescue experiments. Upregulation of NCAPD3 levels in LC tissues was found in Ualcan and significantly associated with poor prognosis. The expression of NCAPD3 was up-regulated in LC cell lines compared to BEAS-2B cells. Knockdown and overexpression experiments suggested that proliferation, apoptosis, migration, invasion, and glycolysis were regulated by NCAPD3 via the MEK/ERK/LDHA pathway. Additionally, NCAPD3 knockdown inhibited tumor growth in vivo. Mechanistically, NCAPD3 overexpression-mediated activation of the MEK/ERK/LDHA pathway and proliferation, Glucose uptake, and glycolysis were attenuated by MEK inhibitor U0126. Also, histone lactylation helps in tumorigenesis by promoting NCAPD3 expression. Taken together, our results revealed that histone lactylation of NCAPD3 promoted proliferation, migration, invasion, and glycolysis through modulating the MEK/ERK/LDHA signaling pathway in LC, which highlights a novel understanding of NCAPD3 in LC.
    Keywords:  Glycolysis; Histone lactylation; Lung cancer; NCAPD3
    DOI:  https://doi.org/10.1186/s12935-025-03814-x
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