bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2025–12–28
six papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. Inhibition of RACGAP1 sensitizes triple-negative breast cancer cells to ferroptosis by regulating CPT1A-dependent fatty acid metabolism.
  2. Extracellular matrix-derived mechanical force induces CDK4/6 inhibitor resistance by inhibiting NEK10 dependent cell cycle regulation in breast cancer.
  3. PR inhibition stimulates G6PD expression to enhance malignancy in luminal breast cancer.
  4. GCDH Promotes Breast Cancer Glutaminolysis Reprogramming by Inducing GLS1 Expression Through Histone Crotonylation at Its Promoter Region.
  5. YAP1 dysfunction promotes molecular properties linked to breast cancer susceptibility.
  6. PAK2 promotes CTC cluster formation by phosphorylating E-cadherin to enhance cell-cell adhesion in breast cancer.
  1. J Exp Clin Cancer Res. 2025 Dec 24. 44(1): 323
    Inhibition of RACGAP1 sensitizes triple-negative breast cancer cells to ferroptosis by regulating CPT1A-dependent fatty acid metabolism.
    Zhike Zhou, Ye Hua, Jun Ma, Wenqiang Cong, Rui Zhan, Kexin Kang, Lu Wang, Hongyi Wei.
       BACKGROUND: Triple-negative breast cancer (TNBC) is highly aggressive tumor with limited therapeutic options. Studying the molecular mechanisms underlying TNBC is necessary to address the unmet need in novel therapeutic targets. TNBC is demonstrated to have robust fatty acid (FA) metabolism activity, and recent studies proposed the linkage of FA metabolism with ferroptosis sensitivity. Hence, this study aimed to explore the targets that may regulate FA metabolism to sensitize TNBC cells to ferroptosis.
    METHODS: RNA-sequencing data in The Cancer Genome Atlas (TCGA) and four microarray datasets in Gene Expression Omnibus (GEO) database were analyzed to identify key target RACGAP1, followed by a series of functional experiments to explore the exact role of RACGAP1 in two TNBC cell lines (human MDA-MB-231 and mouse 4T1) and Xenograft tumor model. Dual-luciferase and chromatin immunoprecipitation (ChIP) assay was utilized to verify the binding of RACGAP1 and MAZ. RNA sequencing on 4T1 cells transfecting with sh-NC and sh-RACGAP1 was performed to validate the actions of RACGAP1.
    RESULTS: RACGAP1 was highly expressed in breast cancer, and associated with poor prognosis and ferroptosis activity. RACGAP1 silencing could inhibit tumor cells survival and promote ferroptosis, and such anti-tumor activity could be blocked by ferroptosis inhibitors. RNA-sequencing analysis suggested that RACGAP1 silencing could inhibit FA metabolism activity, which was further confirmed by metabolic analysis and the reduced level of ATP, triglyceride and FA oxidation. CPT1A overexpression reversed such changes, indicating that the regulation of RACGAP1 on FA metabolism was CPT1A-dependent. Activation of FA metabolism activity or CPT1A overexpression blocked the ferroptosis sensitivity induced by RACGAP1 silencing. Transcription factor MAZ was identified to directly up-regulate the expression of RACGAP1.
    CONCLUSION: Inhibition of RACGAP1 sensitized TNBC cells to ferroptosis by inhibiting CPT1A-mediated FA metabolism. Targeting RACGAP1 might be feasible strategy for TNBC management.
    Keywords:  CPT1A; Fatty acid oxidation; Ferroptosis; MAZ; RACGAP1; Triple-negative breast cancer
    DOI:  https://doi.org/10.1186/s13046-025-03568-4
  2. Int J Surg. 2025 Dec 22.
    Extracellular matrix-derived mechanical force induces CDK4/6 inhibitor resistance by inhibiting NEK10 dependent cell cycle regulation in breast cancer.
    Cong Li, Jian Wang, Yuming Jin, Yumeng Huang, Ruoxi Hong, Dongshao Chen, Shaoyan Lin, Limin Chen, Huailiang Wu, Ting Du, Binghe Xu, Wan Wang, Shusen Wang.
       BACKGROUND: Biomechanical signals play a pivotal role in tumor initiation and progression, with the extracellular matrix (ECM) acting as a key source of these signals. This study aims to investigate the role of ECM-derived biomechanical signals in mediating CDK4/6 inhibitor resistance in HR +, HER2- breast cancer.
    MATERIALS AND METHODS: This study utilized 3D Matrigel, collagen, and fibrin gels to examine the role of ECM-derived biomechanical signals in regulating CDK4/6 inhibitor resistance. Single-cell sequencing data from 23 breast cancer patients were analyzed to explore the core molecular mechanisms underlying this resistance. Transcriptomic analysis and Western blotting were conducted to assess the expression of the NEK10/p53/CDKN1A/CDK2 signaling pathway in breast cancers. Data from 1092 patients in TCGA were also incorporated, alongside a prognostic analysis of 25 clinical samples.
    RESULTS: ECM-derived biomechanical signals suppressed CDK4/6 inhibitor-induced cell cycle arrest and senescence in breast cancer cells, promoting drug resistance. scRNA-seq and tumor tissue analysis identified NEK10 as a key downregulated kinase associated with resistance. Mechanistically, ECM-induced mechanical forces reduced NEK10 expression via a cytoskeleton-dependent pathway, leading to suppression of the NEK10/p53/CDKN1A axis and activation of CDK2 signaling. NEK10-deficient cells and organoids displayed enhanced resistance to Palbociclib, which was reversed by co-treatment with the CDK2 inhibitor. In vivo, combined inhibition of CDK4/6 and CDK2 significantly improved therapeutic efficacy in NEK10-low breast cancer.
    CONCLUSION: This study underscores the critical role of ECM-derived biomechanical forces in regulating CDK4/6 inhibitor resistance in breast cancer and identifies NEK10 as a potential therapeutic target for improving breast cancer treatment.
    Keywords:  CDK4/6 inhibitor; NEK10; biomechanical force; cell cycle; extracellular matrix
    DOI:  https://doi.org/10.1097/JS9.0000000000004527
  3. Cell Death Dis. 2025 Dec 21.
    PR inhibition stimulates G6PD expression to enhance malignancy in luminal breast cancer.
    Jae Woong Jeong, Janghee Lee, Soong June Bae, Yoon Jin Cha, Sungsoon Fang, Hae-Kyung Lee, Sung Gwe Ahn.
      Luminal breast cancer is the most prevalent and prognostic subtype of breast cancer. However, it has been reported that luminal breast cancer patients with lower progesterone receptor (PR) expression are associated with poor survival outcomes. Nevertheless, there is insufficient evidence linking PR expression to an aggressiveness of luminal breast cancer. Based on our previous studies showing an inverse correlation between PR and standardized uptake value (SUV) on [18 F] fluorodeoxyglucose positron emission tomography (FDG-PET), we aimed to identify a potential link between PR expression and glucose metabolism, particularly the pentose phosphate pathway (PPP). To investigate it, we performed a single cell RNA sequencing (scRNA-seq) analysis using published dataset. Interestingly, the analysis revealed that specific epithelial cells with both increased proliferation activity and decreased PR expression, which increased activity of the PPP and glucose-6-phosphate dehydrogenase (G6PD) expression. To verify these findings, we silenced PR expression in the luminal breast cancer cell lines, MCF7 and T47D, which led to accelerated proliferation and PPP activity with G6PD expression. We hypothesized that PR knockdown (KD) increases breast cancer aggressiveness by boosting glucose utilization with PPP activity. Importantly, treatment with G6PD inhibitor (G6PDi), a G6PDi reduced aggressiveness of PR KD cancer cells. These findings suggest that targeting G6PD could be a promising therapeutic strategy to suppress the aggressiveness of luminal breast cancer, using low PR expression as a biomarker.
    DOI:  https://doi.org/10.1038/s41419-025-08365-7
  4. Cancer Manag Res. 2025 ;17 3185-3196
    GCDH Promotes Breast Cancer Glutaminolysis Reprogramming by Inducing GLS1 Expression Through Histone Crotonylation at Its Promoter Region.
    Jianan Zhang, Mengsha Zou.
       Objective: Glutaryl-CoA dehydrogenase (GCDH) is a mitochondrial enzyme involved in lysine and tryptophan catabolism, yet its role in cancer metabolism remains poorly understood. This study aimed to investigate the function of GCDH in regulating glutamine metabolism and proliferation in breast cancer cells, and to elucidate its molecular mechanism via epigenetic modulation of glutaminase 1 (GLS1).
    Methods: GCDH expression was silenced using siRNAs in human breast cancer cell lines MCF-7 and MDA-MB-231. Cell proliferation was assessed using CCK-8 and EdU assays. Glutamine metabolism was analyzed by quantifying intracellular levels of glutamine, glutamate, α-ketoglutarate (α-KG), and ATP. In vivo effects were evaluated using a xenograft model in BALB/c nude mice. Chromatin immunoprecipitation (ChIP), luciferase reporter assays, and Western blotting were performed to explore the epigenetic regulation of GLS1. Functional interaction between GCDH and GLS1 was further validated through overexpression and knockdown studies, and the requirement for GCDH's enzymatic activity was tested using a catalytically inactive mutant.
    Results: GCDH knockdown significantly suppressed proliferation in MCF-7 and MDA-MB-231 cells (p<0.001), decreased EdU incorporation (p<0.01), and impaired glutamine metabolism, as indicated by elevated intracellular glutamine and reduced levels of glutamate, α-KG, and ATP (all p<0.05). In vivo, GCDH depletion led to reduced tumor growth and weight (p<0.001), with altered metabolic profiles consistent with impaired glutaminolysis (decreased α-KG, p<0.05). Mechanistically, GCDH silencing reduced global and GLS1 promoter-specific H3K27 crotonylation (p<0.01), suppressing GLS1 transcriptional activity (p<0.001). Overexpression of GLS1 reversed the metabolic and proliferative deficits induced by GCDH knockdown. Furthermore, wild-type GCDH overexpression, but not a catalytically inactive mutant, partially restored glutamate production and ATP levels in GLS1-deficient cells (p<0.05), indicating a functional interplay that depends on GCDH's enzymatic activity.
    Conclusion: GCDH promotes breast cancer cell proliferation and metabolic activity by enhancing glutaminolysis through epigenetic upregulation of GLS1 via histone crotonylation. Critically, this novel metabolic-epigenetic axis requires the catalytic function of GCDH. These findings not only reveal a novel metabolic-epigenetic axis driven by a specific mitochondrial enzyme but also suggest GCDH as a potential therapeutic target in breast cancer.
    Keywords:  breast cancer; epigenetic regulation; glutamine metabolism; histone crotonylation
    DOI:  https://doi.org/10.2147/CMAR.S552195
  5. Cancer Prev Res (Phila). 2025 Dec 23.
    YAP1 dysfunction promotes molecular properties linked to breast cancer susceptibility.
    Tara Fresques, Jennifer C Lopez, Deborah Hussey, Masaru Miyano, James C Garbe, Stefan Hinz, Rosalyn W Sayaman, Aimin Li, Daniel Schmolze, Serenity Van Bedford, Martha R Stampfer, Mark A LaBarge.
      YAP1 is a co-transcription factor that promotes malignant and stem cell properties in cancer. We previously found that YAP1 dysregulation is associated with aging in human mammary epithelia. With increased age, YAP1 expression changes in luminal epithelial cells, the prospective breast cancer cell of origin. Because age is a significant risk factor for breast cancer, we tested if YAP1 dysregulation acted early in cancer progression by conferring cellular states associated with increased cancer susceptibility. Here we find, that with increased age and genetic risk for developing cancer, human breast tissues showed significantly increased YAP1 expression and cultured primary human mammary epithelial cells (HMEC) showed significantly increased expression of both YAP1 and its transcriptional targets. Increased YAP1 expression in cultured HMEC induced gene expression changes associated with increased cancer susceptibility such as genes associated with: stem cell fate, increased telomerase activity, breast cancer progression, and increased age and genetic breast cancer risk. Further, overexpression of YAP1 in post-stasis HMEC- finite lifespan cells which have bypassed a retinoblastoma-mediated senescence barrier- promoted properties related to an increased growth potential. We found that YAP1 dysregulation in finite epithelial cells allows for access to gene programs and functions that are typically thought to be restricted to stem cells. We hypothesize that YAP1 acts early in breast cancer progression, long before development of a tumor, to impose cancer susceptible molecular states.
    DOI:  https://doi.org/10.1158/1940-6207.CAPR-25-0027
  6. Breast Cancer Res. 2025 Dec 21.
    PAK2 promotes CTC cluster formation by phosphorylating E-cadherin to enhance cell-cell adhesion in breast cancer.
    Lihuang Guo, Jiancheng Li, Wenxing Zhu, Zhuo Wang, Youyou Huang, Zhengyang Sun, Yue Huang, Keqian Xu.
       BACKGROUND: Circulating tumor cell (CTC) clusters exhibit significantly greater metastatic potential than single CTCs and are associated with poorer overall survival in cancers. However, the molecular mechanisms driving CTC cluster formation remain unclear. p21-activated kinase 2 (PAK2) plays a critical role in cytoskeletal remodeling and is frequently associated with advanced tumor progression and poor prognosis. In this study, we explored the role of PAK2 in CTC cluster formation in breast cancer.
    METHODS: We performed an integrated bioinformatics analysis of transcriptomic profiles from single CTCs and CTC clusters via GEO datasets to identify differentially expressed genes (DEGs) and candidate hub genes associated with CTC clustering. Functional enrichment analyses and gene set enrichment analysis were subsequently conducted to explore relevant pathways. The biological function of the identified hub gene PAK2 was validated via in vitro CTC cluster formation cell models and in vivo orthotopic in situ breast cancer mouse models. Mechanistic studies focused on PAK2-mediated phosphorylation of E-cadherin. Additionally, the therapeutic potential of targeting PAK2 was evaluated via the use of the selective PAK inhibitor FRAX597 in vivo.
    RESULTS: Bioinformatics analyses revealed that CTC clusters are characterized by enhanced cell-cell adhesion, increased proliferative capacity and survival advantages. Among the identified hub genes, PAK2 was significantly upregulated in breast cancer tissues and cell lines, and its elevated expression was associated with poor patient prognosis. Functional experiments demonstrated that PAK2 promotes CTC cluster formation by increasing E-cadherin phosphorylation at Ser840, thereby strengthening cell-cell adhesion. Pharmacologic inhibition of PAK2 with FRAX597 impaired CTC cluster formation, suppressed tumor growth, reduced metastasis and decreased CTC cluster numbers in vivo.
    CONCLUSIONS: This study revealed that PAK2 promotes CTC cluster formation and breast cancer metastasis by enhancing E-cadherin-mediated cell-cell adhesion. These results provide novel insights into the molecular mechanisms underlying CTC cluster formation and highlight PAK2 as a potential therapeutic target and diagnostic marker for preventing breast cancer metastasis.
    Keywords:  Breast cancer; CTC cluster; Cell adhesion; E-cadherin; Metastasis; PAK2
    DOI:  https://doi.org/10.1186/s13058-025-02199-z
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