bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2026–04–12
seven papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. Proteomic Signatures of Adipocyte Recruitment in Breast Cancer.
  2. JMJD3 regulates the M2-like macrophage polarization and promotes the growth of breast cancer cells via STAT6/IRF4 axis.
  3. Nuclear FGF2, androgen receptor and Wnt pathway activation define a targetable subset of antiprogestin-resistant luminal breast cancer.
  4. Novel SOAT inhibitors block DHEAS transport and suppress proliferation in MCF-7 breast cancer cells.
  5. Comparative omics reveals conserved extracellular matrix signatures during mammary tumor progression.
  6. Targeting the tripartite axis of immune-metabolic-spatial crosstalk to overcome therapy resistance in breast cancer.
  7. Perilipin 5 enhances glycogen storage and mitigates excessive fatty acid oxidation in skeletal muscle to alleviate mitochondrial impairment.
  1. Endocr Relat Cancer. 2026 Apr 09. pii: ERC-25-0361. [Epub ahead of print]
    Proteomic Signatures of Adipocyte Recruitment in Breast Cancer.
    Dimitrios G Argyris, Ioanna Ploumaki, Theodora Argyri, Dimitra P Anastasiadou, Nikos S Karagiannis, Maria P Pavlou, Evanthia T Roussos-Torres, Outhiriaradjou Benard, Rachel B Hazan, Panagiota S Filippou, George S Karagiannis.
      The tumor microenvironment (TME) is increasingly recognized as a dynamic regulator of breast cancer progression, with adipocytes functioning as active contributors rather than passive bystanders. Here, we investigated the proteomic and morphologic reprogramming of breast cancer-associated adipocytes (BrCAAs) in response to triple-negative breast cancer (TNBC). Using conditioned medium from HCC1143 cells, we established an in vitro BrCAA model and performed mass spectrometry-based proteomics. Comparative profiling revealed 256 differentially expressed proteins, enriched for pathways including fatty acid degradation, carbon metabolism, and glycogen turnover, consistent with a metabolic shift from energy storage to energy supply. Gene ontology and protein-protein interaction analyses further identified cytoskeletal remodeling, adhesion dynamics, and secretory pathway activation, supporting BrCAA-driven microenvironmental remodeling. In the MMTV-PyMT mouse model, morphometric analysis demonstrated progressive size reduction and increased contour irregularity of adipocytes adjacent to tumors, correlating with proteomic evidence of metabolic stress. Importantly, BrCAAs localized at tumor interfaces were associated with increased microvessel density and CD105+ endothelial activation compared to desmoplastic zones. Proteomic enrichment highlighted pro-angiogenic remodeling, with validation of Basigin (BSG), Integrin αV (ITGAV), and 2,4-dienoyl-CoA reductase 1 (DECR1). Collectively, our findings establish BrCAAs as metabolically and structurally reprogrammed stromal components that promote tumor metabolism and localized angiogenesis, representing potential therapeutic targets in aggressive breast cancer.
    Keywords:  Angiogenesis; breast cancer; cancer-associated adipocytes; metabolic reprogramming; proteomics; tumor microenvironment
    DOI:  https://doi.org/10.1530/ERC-25-0361
  2. PLoS One. 2026 ;21(4): e0341313
    JMJD3 regulates the M2-like macrophage polarization and promotes the growth of breast cancer cells via STAT6/IRF4 axis.
    Juan Lyu, Enqin Wang, Shanmei Lyu, Ying Qian, Fen Ye, Xiuping Xu, Qing Wang, Tao Lu, Liangfeng Hu, Hongkun Xu, Lihong Zhang.
      M2-like macrophages play a critical role in breast cancer progression. Although JMJD3 is reported to play a significant role in M2-like macrophage polarization, its precise mechanism remains unclear. By using PMA, IL-4, and IL-13, we successfully induced THP-1 cells into M2-like macrophages, which subsequently promoted breast cancer cell proliferation and inhibited apoptosis, accompanied by increased JMJD3 expression. We demonstrated that JMJD3 enhances M2-like macrophage polarization: knockdown of JMJD3 decreased the M2-like macrophage gene expression, while overexpression of JMJD3 produced the opposite effects. Furthermore, JMJD3 promoted M2-like macrophage polarization through the STAT6/IRF4 axis. Knockdown of JMJD3 abrogated IL-4/IL-13 induced IRF4 expression, while overexpression of JMJD3 upregulated IRF4 expression. Inhibition of STAT6 downregulated the expression of JMJD3, IRF4, and M2-like macrophage marker genes. Additionally, inhibiting JMJD3 and STAT6 in macrophages increased cell apoptosis and decreased cell viability in breast cancer cells, while JMJD3 overexpression exhibited pro-tumor activity. In conclusion, our findings highlight the role of JMJD3 in regulating M2-like macrophage polarization and its impact on breast cancer development through the STAT6/IRF4 axis.
    DOI:  https://doi.org/10.1371/journal.pone.0341313
  3. Br J Cancer. 2026 Apr 04.
    Nuclear FGF2, androgen receptor and Wnt pathway activation define a targetable subset of antiprogestin-resistant luminal breast cancer.
    Virginia Figueroa, Marcela I Coianis, Ana Sahores, Gabriela Pataccini, Martín C Abba, Andrés Elía, María May, Silvia I Vanzulli, Paula Martínez Vázquez, Javier Burruchaga, Florencia Torres, Carol A Sartorius, Claudia Lanari, Caroline A Lamb.
       BACKGROUND: Endocrine resistance is a major clinical challenge in luminal breast cancer. Nuclear fibroblast growth factor 2 (FGF2) and altered progesterone receptor (PR) isoform ratios have been identified as markers of antiprogestin resistance. We investigated pathways associated with FGF2 upregulation to identify new targets for antiprogestin-resistant tumours.
    METHODS: PR+ T47D and T47D‑YA cell lines engineered to overexpress FGF2 were used to investigate FGF2‑driven antiprogestin resistance. Transcriptome profiling, qRT-PCR, immunohistochemistry, and in vivo assays assessed hormone receptor expression, pathway alterations, and therapeutic response. We evaluated nuclear androgen receptor (AR) and FGF2 in luminal breast cancer specimens.
    RESULTS: RNA-seq showed that FGF2 overexpression dysregulated Wnt signalling, downregulated oestrogen receptor (ER) and PR, and upregulated AR expression. PR isoform B (PRB) predominated, consistent with an antiprogestin-resistant phenotype. FGF2-overexpressing xenografts showed antiprogestin resistance, increased proliferation, and lung metastasis. AR and Wnt pathway blockade impaired tumour growth, and combined treatment further reduced tumour and metastatic burden. In clinical samples, nuclear FGF2 correlated with elevated AR levels in ER+PR- and PRB-high tumours.
    CONCLUSION: We identified a subset of luminal breast cancers characterised by nuclear FGF2, AR upregulation, and PR isoform imbalance. Dual AR and Wnt pathway targeting may offer a promising strategy for antiprogestin-resistant disease.
    DOI:  https://doi.org/10.1038/s41416-026-03420-2
  4. Sci Rep. 2026 Apr 10. pii: 12016. [Epub ahead of print]16(1):
    Novel SOAT inhibitors block DHEAS transport and suppress proliferation in MCF-7 breast cancer cells.
    Emre Karakus, Silke Leiting, Michael Daude, Wibke E Diederich, Joachim Geyer.
      Intracrine estrogen formation from adrenal precursors such as dehydroepiandrosterone sulfate (DHEAS) plays a critical role in sustaining estrogen receptor (ER)-positive breast cancer cell proliferation, particularly in postmenopausal women. The sodium-dependent organic anion transporter (SOAT, gene symbol SLC10A6) facilitates the cellular uptake of sulfated steroids, thereby making these precursors available for local estrogen biosynthesis. However, the impact of SOAT inhibition on intracrine estrogen metabolism in breast cancer remains unclear. We investigated the effects of pharmacological SOAT inhibition on SOAT-mediated DHEAS transport, cell proliferation and intracrine estradiol synthesis in SOAT-overexpressing MCF-7 breast cancer cells (MCF-7_SOAT). These MCF-7_SOAT cells were treated with the SOAT inhibitor S1647, as well as two newly synthesized derivatives (compounds 12 and 24) that exhibit enhanced selectivity and potency. DHEAS uptake and downstream steroid metabolism were quantified using LC-MS/MS, while DHEAS-induced cell proliferation was analyzed using [³H]thymidine incorporation. SOAT inhibition markedly reduced sodium-dependent DHEAS uptake, resulting in decreased intracellular estradiol synthesis and suppression of estrogen-dependent proliferation without cytotoxicity. These findings confirm that SOAT is a critical upstream regulator of intracrine estrogen biosynthesis in breast cancer cells and highlight compounds 12 and 24 as promising candidates for further preclinical development aimed at reducing local estrogen production.
    Keywords:  Breast cancer; DHEAS transport; Endocrine therapy; Intracrine estrogen formation; MCF-7 cells; SOAT (SLC10A6)
    DOI:  https://doi.org/10.1038/s41598-026-47803-0
  5. Front Oncol. 2026 ;16 1788746
    Comparative omics reveals conserved extracellular matrix signatures during mammary tumor progression.
    Bruno Sousa de Almeida, Gisele Vieira Rocha, Simone Nunes, Dalila Luciola Zanette, Michel Batista, Alessandra Estrela-Lima, Carlos Gustavo Regis-Silva, Karine Araújo Damasceno.
      The extracellular matrix (ECM) plays a critical role in tumor progression by modulating cell adhesion, migration, and signaling; however, its contribution to metastatic progression in spontaneous mammary tumors remains poorly understood. Mammary tumors are among the most common neoplasms in female dogs and share histopathological and molecular similarities with human breast cancer, supporting their use as a comparative oncology model. To investigate ECM remodeling during tumor progression, we analyzed normal, non-metastatic, and metastatic canine mammary tissues using histological approaches and label-free quantitative proteomics. Publicly available human breast cancer transcriptomic datasets were interrogated for in silico validation of conserved molecular signatures. Proteomic profiling identified 12 differentially expressed ECM-related proteins: eight were upregulated (COL12A1, COL4A1, COL4A2, SERPINH1, SERPINF1, HTRA1, TNC, PCOLCE) and four were downregulated (MMRN1, ABI3BP, DPT, OGN). The downregulated proteins were further validated in human breast cancer transcriptomes. Collectively, these findings indicate active ECM remodeling during tumor progression, characterized by increased expression of proteins associated with matrix stiffness and invasiveness. This study highlights evolutionarily conserved mechanisms of ECM dysregulation in breast cancer and identifies potential matrix targets for translational research and biomarker development.
    Keywords:  Comparative oncology; extracellular matrix; mammary tumor; proteomics; tumor progression
    DOI:  https://doi.org/10.3389/fonc.2026.1788746
  6. Front Immunol. 2026 ;17 1748257
    Targeting the tripartite axis of immune-metabolic-spatial crosstalk to overcome therapy resistance in breast cancer.
    Siyu He, Xuyan Liu, Qingjie Lv.
      Therapeutic resistance remains the principal cause of mortality in breast cancer. While the tumor microenvironment (TME) is a key contributor, therapies targeting isolated TME components, whether immune, metabolic, or spatial, have largely failed due to compensatory adaptations and ecological resilience. This review synthesizes recent advances to propose a tripartite "Immune-Metabolic-Spatial" axis as the fundamental organizer of a robust resistance niche. We elucidate how immunosuppressive cells, such as TAMs and Tregs, are metabolically sustained by altered nutrient availability like lactate and hypoxia, while spatial constraints, including CAF-deposited ECM and DDR1-mediated collagen alignment, physically impede drug delivery and immune infiltration. Critically, we highlight reciprocal crosstalk where metabolic reprogramming dictates immune cell function, in turn influencing stromal remodeling to create a self-reinforcing resistance loop. Beyond mechanism, we evaluate emerging strategies that concurrently target multiple axes, such as combining immune checkpoint blockade with metabolic inhibitors or stromal disruptors. Finally, we discuss clinical translation through biomarker development and innovative trial designs, framing the tripartite axis as an actionable framework for overcoming therapeutic resistance.
    Keywords:  breast cancer; drug resistance; immune regulation; metabolic reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1748257
  7. Biochim Biophys Acta Mol Cell Res. 2026 Apr 08. pii: S0167-4889(26)00043-1. [Epub ahead of print] 120146
    Perilipin 5 enhances glycogen storage and mitigates excessive fatty acid oxidation in skeletal muscle to alleviate mitochondrial impairment.
    Yuqiao Xu, Xing Gao, Shenhui Xu, Lele Jian, Jiankkuan Shi, Yuanlin Zhao, Yuying Wang, Ying Yang, Yuan Yuan, Qiulong Dai, Qian Zhang, Jing Li, Lijun Zhang.
      Perilipin 5 (Plin5) is a lipid droplet-associated protein that regulates lipid hydrolysis and mitochondrial oxidative metabolism, and is highly expressed in skeletal muscle. Its role in skeletal muscle glucose metabolism and its relevance to mitochondrial myopathy (MM) remain unclear. We used Plin5-knockout (Plin5-KO) mice in exhaustive swimming tests to assess endurance and anaerobic exercise capacity. Glucose uptake was measured using 2-NBDG; glucose, lactate, NADH/NAD+ ratio, and fatty acid oxidation (FAO) rate were determined with commercial kits. Mitochondrial ultrastructure was evaluated via electron microscopy, and immunoblotting was used to assess proteins related to glucose-lipid metabolism. Muscle biopsies from 26 patients with mitochondrial myopathy were examined morphologically and for Plin5 expression by immunohistochemistry. Plin5-KO mice showed impaired anaerobic capacity, markedly reduced glycogen storage (especially after-exercise), increased lactate production, and reduced AKT phosphorylation, indicating insulin resistance. Mechanistically, Plin5 deficiency promoted excessive FAO, worsened mitochondrial damage, and elevated the NADH/NAD+ ratio, shifting glucose metabolism toward anaerobic glycolysis with excess lactate output. In contrast, Plin5 overexpression improved insulin sensitivity and reduced FAO in skeletal muscle cells. In MM patients, Plin5 expression in skeletal muscle tended to be negatively associated with blood lactate levels. These findings indicate that Plin5 may play a crucial role in improving glycolipid metabolism and protecting mitochondrial function by enhancing glycogen storage and reducing excessive FAO in skeletal muscle cells.
    Keywords:  Insulin resistance; Lactate; Mitochondrial dysfunction; Myopathy; NADH/NAD+; Perilipin 5
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120146
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