bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2025–07–20
nine papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. Fibroblast growth factor receptor signaling modulates cholesterol storage in a SOAT1-dependent manner to promote mammary tumor cell invasion.
  2. Metabolomic Profiling Reveals Key Metabolic Alterations in MCF7 Tamoxifen-Resistant Cells Following EPAS1 Inhibition.
  3. Brain FGF2 and NCAM1 contribute to FGFR1-dependent progression of ER+ breast cancer brain metastases in young and aged hosts.
  4. E2F7 transcriptionally upregulates SPC24 to mediate aerobic Glycolysis and facilitate stemness of breast cancer.
  5. Soluble E-cadherin Drives Brain Metastasis in Inflammatory Breast Cancer.
  6. HIF-1 promotes murine breast cancer brain metastasis by increasing production of integrin β3-containing extracellular vesicles.
  7. Correlation between CTMP expression levels and resistance to trastuzumab in HER2 + metastatic breast cancer.
  8. CDH1 loss remodels gene expression and lineage identity in human mammary epithelial cells.
  9. Obesity-cancer axis crosstalk: Molecular insights and therapeutic approaches.
  1. Breast Cancer Res. 2025 Jul 15. 27(1): 132
    Fibroblast growth factor receptor signaling modulates cholesterol storage in a SOAT1-dependent manner to promote mammary tumor cell invasion.
    Jennifer E Tuokkola, Lyndsay E Reese, Ying Wang, Christine H O'Connor, Jillian G VanTreeck, Annisa H Rumahorbo, Kathryn L Schwertfeger.
      Signaling by fibroblast growth factor receptors (FGFRs) is active in up to 85% of breast cancers and results in enhanced proliferation, migration, and invasion of tumor cells. Here, we show that FGFR signaling regulates cholesterol metabolism in breast cancer. Specifically, we demonstrate that FGFR activation promotes cellular cholesterol storage by upregulating expression of the enzyme sterol O-acyltransferase 1 (SOAT1). Moreover, we demonstrate that inhibition of SOAT1 attenuates FGFR-driven colony formation and invasion in tumor cells, which correlates with reduced expression of matrix metalloproteinase expression. Furthermore, genetic knockdown of SOAT1 decreases mammary tumor growth in vivo. Taken together, these findings suggest a largely undiscovered metabolic role for FGFR signaling in regulating cholesterol metabolism in breast cancer and present a therapeutic vulnerability that could be targeted in FGFR-driven cancers.
    Keywords:  Cholesterol metabolism; Cholesterol storage; Fibroblast growth factor; Triple-negative breast cancer
    DOI:  https://doi.org/10.1186/s13058-025-02084-9
  2. J Proteome Res. 2025 Jul 17.
    Metabolomic Profiling Reveals Key Metabolic Alterations in MCF7 Tamoxifen-Resistant Cells Following EPAS1 Inhibition.
    Enzhi Luo, Neeraj Manvi Agarwal, Junjeong Choi.
      Tamoxifen (TAM) is a frontline therapy for luminal A breast cancer, yet acquired resistance poses a significant clinical challenge. This study investigates the molecular and metabolic basis of TAM resistance in MCF7/Tam1 cells, focusing on EPAS1 (HIF-2α)-driven hypoxia-induced metabolic reprogramming and the potential of the EPAS1 inhibitor PT2977 to restore TAM sensitivity. Comparative transcriptomic analysis revealed upregulation of EPAS1 along with enrichment of hypoxia-associated pathways, including JAK-STAT, TGF-beta, and lipid metabolism in resistant cells. Untargeted LC-MS/MS metabolomics identified 1,039 significantly altered metabolites, with notable dysregulation in glutamate and glutathione metabolism, the Warburg effect, and fatty acid oxidation. Mechanistically, EPAS1 promoted fatty acid uptake via CD36 and enhanced glutamine metabolism through SLC1A5, contributing to redox balance and cell survival under TAM stress. Treatment with PT2977 disrupted these metabolic pathways, as evidenced by PCA and Venn analyses, leading to a dose-dependent normalization of metabolite profiles and selective reduction in cell viability. These findings highlight EPAS1-mediated metabolic reprogramming as a key driver of TAM resistance and support EPAS1 inhibition by PT2977 as a promising therapeutic strategy to overcome resistance in luminal A breast cancer.
    Keywords:  EPAS1; PT2977; hypoxia; metabolomics.; tamoxifen resistance
    DOI:  https://doi.org/10.1021/acs.jproteome.5c00170
  3. bioRxiv. 2025 Jun 16. pii: 2025.06.07.658373. [Epub ahead of print]
    Brain FGF2 and NCAM1 contribute to FGFR1-dependent progression of ER+ breast cancer brain metastases in young and aged hosts.
    Morgan S Fox, Jenny A Jaramillo-Gómez, R Alejandro Marquez-Ortiz, Karen L F Alvarez-Eraso, Maria J Contreras-Zárate, Stella Koliavas, Peter Kabos, Natalie J Serkova, Carol A Sartorius, Elizabeth A Wellberg, Diana M Cittelly.
      Estrogen receptor positive (ER+) breast cancer (BC) represents a significant proportion of BC brain metastasis (BCBM) but remains understudied. Here, we report that FGFR1-amplification, a well-established driver of ER+ BC endocrine resistance, promotes ER+ BCBM colonization in young and aged mice, through brain-dependent mechanisms. FGFR1-dependent brain colonization in young and aged mice occurs via canonical FGF2/FGFR1 signaling and non-canonical NCAM1/FGFR1 interactions. Astrocytic FGF2-mediated paracrine activation of FGFR1 promoted BCBMs in estrogen-treated young mice, but FGF2 signaling decreased in the brain with aging and estrogen-depletion. Neuronal and glial NCAM1, which remain unchanged in young and aged brains, promoted adhesion to neurons and migration of ER+ BC cells, suggesting that interactions with astrocytes and neurons facilitate early ER+ BCBM colonization through FGFR1. Importantly, FDA-approved FGFR inhibitors effectively blocked early but not late metastatic progression only in young mice, suggesting limited efficacy of FGFR inhibitors to block non-kinase-dependent FGFR1 functions in vivo .
    DOI:  https://doi.org/10.1101/2025.06.07.658373
  4. J Bioenerg Biomembr. 2025 Jul 15.
    E2F7 transcriptionally upregulates SPC24 to mediate aerobic Glycolysis and facilitate stemness of breast cancer.
    Wen Yun, Changfei Mao, Yuan Yuan.
      Metabolic reprogramming characterized by aerobic glycolysis is observed in various cancers, including breast cancer (BC), exerting essential influence on maintaining cancer stemness. The abnormal expression of SPC24 is linked to the occurrence and development of various cancers, but its role in BC remains unelucidated. Bioinformatics analysis was undertaken to determine the levels of SPC24 and E2F7 in BC, and the enriched signaling pathways of SPC24 with differential expression, which were validated through cell experiments. The transcriptional regulatory relationship between E2F7 and SPC24 was also assessed through bioinformatics analysis, with validation completed by dual luciferase assay and chromatin immunoprecipitation (ChIP). To evaluate BC stemness, we employed the western blot (WB) to detect the levels of CD44, CD133, Oct-4, and ALDH1A1, and conducted the cell sphere formation. Flow cytometry was used to detect the proportion of stem cells. To assess the level of glycolysis in BC cells, we detected the expression of key proteins LDHA, HK2, and GLUT1 through WB, and measured the extracellular acidification rate and oxygen consumption rate with kits. Cell experiments combining bioinformatics analysis demonstrated that both E2F7 and SPC24 were greatly upregulated in BC, with SPC24 primarily enriched in the glycolysis metabolic pathway. Further experiments manifested that SPC24 reinforced cell stemness through aerobic glycolysis reprogramming, and SPC24 was modulated by transcription factor E2F7. E2F7 transcriptionally activates the upregulation of SPC24 in BC, which boosts stemness through aerobic glycolysis reprogramming.
    Keywords:  Breast cancer; E2F7; Glycolysis; SPC24; Stemness
    DOI:  https://doi.org/10.1007/s10863-025-10066-x
  5. bioRxiv. 2025 Jun 24. pii: 2025.06.18.660428. [Epub ahead of print]
    Soluble E-cadherin Drives Brain Metastasis in Inflammatory Breast Cancer.
    MDACC Inflammatory Breast Cancer Team
      The brain is a common site of relapse in inflammatory breast cancer (IBC), an E-cadherin positive, aggressive form of breast cancer. We found that elevated serum levels of soluble E-cadherin (sEcad), an 80-kDa fragment of E-cadherin, in patients with metastatic IBC correlated with poorer outcomes and increased rates of brain metastases. In our effort to understand the underlying mechanism, we discovered that sEcad binds to XIAP, an inhibitor of cell death, activating the pro-survival NF-kβ signaling in tumor cells. We also discovered that sEcad affects the tumor cell microenvironment by enhancing cancer cell adhesion to endothelial cells and inducing reactive astrocytosis in the brain. In addition, we found that sEcad-mediated reactive astrocytosis relies on the CXCL1/CXCL8-CXCR2 axis and treatment with a brain-permeable CXCR2 antagonist reduced brain metastatic burden and prolonged survival. These findings implicate sEcad in brain metastasis and provide new insights into potential therapeutic targets for IBC.
    Highlights: High serum sEcad levels correlate clinically with poor survival outcomes and development of brain metastasissEcad drives IBC brain metastasis growth in mouse modelssEcad binds XIAP to activate NFkB and promote anoikis resistance and invasion of IBC cells sEcad activates reactive astrocytes and induces CXCR2 expression on tumor cells in vitro and in vivo CXCR2-IN-1, a brain-permeable CXCR2 antagonist, reduces metastasis and improves survival in IBC brain metastasis models.
    DOI:  https://doi.org/10.1101/2025.06.18.660428
  6. J Clin Invest. 2025 Jul 15. pii: e190470. [Epub ahead of print]135(14):
    HIF-1 promotes murine breast cancer brain metastasis by increasing production of integrin β3-containing extracellular vesicles.
    Yongkang Yang, Chelsey Chen, Yajing Lyu, Olesia Gololobova, Xin Guo, Tina Yi-Ting Huang, Vijay Ramu, Varen Talwar, Elizabeth E Wicks, Shaima Salman, Daiana Drehmer, Dominic Dordai, Qiaozhu Zuo, Kenneth W Witwer, Kathleen L Gabrielson, Gregg L Semenza.
      Brain metastasis is a major cause of breast cancer (BC) mortality, but the cellular and molecular mechanisms have not been fully elucidated. BC cells must breach the blood-brain barrier in order to colonize the brain. Here, we determined that integrin β3 (ITGB3) expression mediated by hypoxia-inducible factor 1 (HIF-1) plays a critical role in metastasis of BC cells to the brain. Hypoxia stimulated BC cell migration and invasion ex vivo and brain colonization in vivo. Knockdown of either HIF-1α or ITGB3 expression impaired brain colonization by human or mouse BC cells injected into the cardiac left ventricle. Exposure of BC cells to hypoxia increased expression of ITGB3 and its incorporation into small extracellular vesicles (EVs). EVs harvested from the conditioned medium of hypoxic BC cells showed increased retention in the brain after intracardiac injection that was HIF-1α and ITGB3 dependent. EVs from hypoxic BC cells showed binding to brain endothelial cells (ECs), leading to increased EC-BC cell interaction, increased vascular endothelial growth factor receptor 2 signaling, increased EC permeability, and increased transendothelial migration of BC cells. Taken together, our studies implicate HIF-1-stimulated production of ITGB3+ EVs as a key mechanism by which hypoxia promotes BC brain metastasis.
    Keywords:  Breast cancer; Hypoxia; Oncology; Vascular biology
    DOI:  https://doi.org/10.1172/JCI190470
  7. Discov Oncol. 2025 Jul 16. 16(1): 1342
    Correlation between CTMP expression levels and resistance to trastuzumab in HER2 + metastatic breast cancer.
    Mania Makhoul, Maher Saifo, Fariz Ahmad, Jumana Saleh.
       BACKGROUND: The combination of trastuzumab and chemotherapeutic drugs improves the prognosis of patients with metastatic disease and reduces the mortality. However, trastuzumab resistance has limited the remarkable improvement of this drug. The carboxyl-terminal modulator protein (CTMP) is involved in the regulation of various cancers through positive or negative regulation of Akt. In the HER2-positive SkBR3 breast cancer cell line, CTMP overexpression increases Akt phosphorylation at Thr308 and Ser473. Therefore, CTMP might mediate trastuzumab resistance. The main objective of the paper is to explore the role of CTMP in trastuzumab efficacy in HER2 + metastatic breast cancer (MBC) patients.
    PATIENTS & METHODS: Ninety-six patients received trastuzumab in combination with chemotherapy or hormonal therapy until disease progression. The overall responses of all the patients were assessed as follows: complete response (n = 5), partial response (n = 36), stable disease (n = 24), and progressive disease (n = 31).
    RESULTS: Immunohistochemistry (IHC) staining was carried out to identify CTMP expression in formalin-fixed paraffin-embedded (FFPE) archival tissue blocks. 58 cases had high CTMP expression levels and 38 cases had low CTMP expression levels. The Mann-Whitney U test showed that CTMP expression was markedly higher in trastuzumab non-responders than in trastuzumab responders (P = 0.039). In addition, high CTMP expression was a strong and independent predictor of shorter recurrence-free survival in patients with metastatic breast cancer, as determined by the Kaplan-Meier method.
    CONCLUSIONS: Based on the results, further examination of CTMP in HER2-enriched (MBC) tissue samples could be helpful in predicting patients at risk of tumor progression and trastuzumab resistance.
    Keywords:  CTMP; Metastatic breast cancer; Trastuzumab resistance
    DOI:  https://doi.org/10.1007/s12672-025-03210-x
  8. bioRxiv. 2025 Jun 22. pii: 2025.06.20.660633. [Epub ahead of print]
    CDH1 loss remodels gene expression and lineage identity in human mammary epithelial cells.
    Maggie Musick, Chinasa A Ufondu, Carmen E Rowland, Joseph L Sottnik, Madeleine T Shackleford, Camryn S Nesiba, Julie H Ostrander, Matthew J Sikora.
      Invasive lobular carcinoma (ILC) is a common subtype of breast cancer that is defined in part by genetic loss of CDH1 caused by mutation or deletion, leading to loss of cell adhesion protein E-cadherin in >90% of ILC. Genetic loss of CDH1 is an early event in ILC oncogenesis, yet the mechanisms by which CDH1/ E-cadherin acts as a tumor suppressor are not well understood. To study how early CDH1 loss drives ILC oncogenesis, we used a series of non-transformed human mammary epithelial cell (HMEC) models to target CDH1 /E-cadherin, inhibiting extracellular E-cadherin signaling using antibodies versus modeling genetic CDH1 loss using siRNA or knockout via CRISPR/Cas9. Through transcriptome analyses across four HMEC models, we found that the mode of E-cadherin loss or suppression is critical for the subsequent phenotype. Antibody-mediated inhibition of cell-cell contacts induced gene signatures of epithelial-mesenchymal transition (EMT), consistent with the role of E-cadherin suppression during the EMT process. Conversely, genetic CDH1 loss - as in ILC oncogenesis - repressed EMT signatures, and instead remodeled gene expression toward a luminal epithelial phenotype. Using single cell transcriptomics and flow cytometry analyses of cell lineage markers, we found that genetic loss of CDH1 reprogrammed cells to a luminal progenitor-like phenotype. By isolating luminal versus basal cells prior to CDH1 knockout, we found that CDH1 loss led to remodeling of lineage identity in both populations, converging on a new lineage homeostasis with a luminal progenitor-like phenotype. Consistent with increased progenitor features, CDH1 loss enhanced proliferative capacity over the finite lifespan of the HMECs, highlighting a feature of early CDH1 loss that may contribute to clonal advantage during tumor initiation. Our findings support that inhibition of E-cadherin results in different transcriptional response compared to CDH1 loss, with the latter driving a transcriptional and phenotypic state characteristic of a luminal progenitor-like population, which offers new insight into early events in ILC oncogenesis.
    DOI:  https://doi.org/10.1101/2025.06.20.660633
  9. Acta Pharm Sin B. 2025 Jun;15(6): 2930-2944
    Obesity-cancer axis crosstalk: Molecular insights and therapeutic approaches.
    Ahmed Rakib, Md Abdullah Al Mamun, Mousumi Mandal, Priti Sinha, Udai P Singh.
      Now recognized as a global health crisis, obesity has been linked to an increased risk of many types of cancer, including those of the breast, colon, rectum, uterus, gallbladder, and ovary. Obesity and cancer share several characteristics at the cellular, molecular, and epigenetic levels. Obesity is characterized by chronic inflammation of the adipose tissue (AT), resulting in genotoxic stress that further induces metabolic complications and contributes to the initiation and progression of cancer. The excessive accumulation of AT provides adipokines and lipids to engage tumor cells with stromal and immune cells to infiltrate carcinomas and secrete a plethora of cytokines, chemokines, and growth factors within the tumor microenvironment (TME) that contribute to carcinogenesis. Obesity also alters the metabolic reprogramming of immune cells, including macrophages, neutrophils, and T cells, thereby providing a suitable environment for the growth and progression of cancer. Obesity-associated metabolic dysregulation also perturbs the gut microbiome, which produces metabolites that can further increase the risk of cancer progression. This review will discuss links between obesity and cancer progression, including several crucial pathways that bridge the crosstalk between obesity-associated changes in AT inflammation, immune cells, adipokines, chemokines, and tumor cells to support cancer progression. We will also discuss our insights into the mechanisms by which obesity-driven factors influence metabolic reprogramming and touch base on how obesity mediates microbiome dysbiosis to alter metabolite and affect cancer progression. Altogether, this review highlights the crossroads of the obesity-cancer axis, describes its salient features, and presents possible therapeutic approaches for obesity-related cancers.
    Keywords:  Adipokines; Adipose tissue; Cancer; Glucagon-like peptide-1; Metabolic reprogramming; Metabolism; Microbiome; Obesity
    DOI:  https://doi.org/10.1016/j.apsb.2025.04.029
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