bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2026–05–31
eight papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. Brain FGF2 and NCAM1 contribute to FGFR1-dependent progression of estrogen receptor-positive breast cancer brain metastases.
  2. PSMB1 screened by CRISPR-CAS9 promoted breast cancer progression via PI3K-AKT-mTOR signaling.
  3. Integrating network pharmacology with ex-vivo analysis to assess the effect of IL-2 in halting breast cancer: involvement of Treg/CTLA-4/Blimp-1/caspase-3.
  4. Cannabidiol enhances tamoxifen efficacy via CREB-mediated suppression of ERα signaling in ER-positive breast cancer cells.
  5. Tamoxifen Modulates Actin Stress Fibre Dynamics Through c-Src-MLCK Signalling in Breast Cancer Cells.
  6. Exosomal MicroRNAs as Drivers of Desmoplasia and Treatment Resistance in Breast Cancer: Mechanisms, Biomarker Potential, and Therapeutic Opportunities.
  7. CAFs and Endocrine Therapy Resistance in Hormone Receptor-Positive Breast Cancer.
  8. Mitochondrial gene APOO reprograms lipid metabolism to influence the prognosis of breast cancer.
  1. Nat Commun. 2026 May 28.
    Brain FGF2 and NCAM1 contribute to FGFR1-dependent progression of estrogen receptor-positive breast cancer brain metastases.
    Morgan S Fox, Jenny A Jaramillo-Gómez, R Alejandro Marquez-Ortiz, Karen L F Alvarez-Eraso, Maria J Contreras-Zárate, Trinh C Pham, Elaina N Barela, Stella N Koliavas, Peter Kabos, Natalie J Serkova, Carol A Sartorius, Elizabeth A Wellberg, Diana M Cittelly.
      Estrogen receptor-positive breast cancer represents a significant proportion of breast cancer brain metastasis but remains understudied. Here we show that FGFR1-amplification, a well-established driver of estrogen receptor-positive breast cancer endocrine resistance, promotes estrogen receptor-positive breast cancer brain metastatic colonization in young and aged female mice, through both canonical FGF2/FGFR1 signaling and non-canonical NCAM1/FGFR1 interactions. Astrocytic FGF2-mediated paracrine activation of FGFR1 promotes breast cancer brain metastasis in estrogen-treated young mice, but FGF2 levels and signaling decrease in the brain with aging and estrogen-depletion. Neuronal and astrocytic NCAM1, which remain unchanged in young and aged brains, promote adhesion to neurons, migration, and growth of estrogen receptor-positive cells, suggesting that interactions with astrocytes and neurons facilitate early estrogen receptor-positive breast cancer brain metastasis colonization through FGFR1. Importantly, FDA-approved FGFR inhibitors effectively block early colonization but not late-stage brain metastases, suggesting prevention of FGFR1+ brain metastases as a window of opportunity for FGFR1 inhibitors.
    DOI:  https://doi.org/10.1038/s41467-026-73726-5
  2. Discov Oncol. 2026 May 24.
    PSMB1 screened by CRISPR-CAS9 promoted breast cancer progression via PI3K-AKT-mTOR signaling.
    Lu-Wen Chen, Jing Ning, Yong-Qiang Ye, Hua-Bin Ye, Hui Zeng, Li-Juan Wang.
       BACKGROUND: Breast cancer is a threat to women's health worldwide. Recent studies have focused on the role of differentially expressed genes in tumors. PSMB1 has been reported to play an important role in tumors, however, its role in breast cancer has not been well defined.
    METHODS: The CRISPR-CAS9 data was analyzed and intersected with Cox univariate analyzation to screen differentially expressed genes in breast cancer. The prognosis of PSMB1 was predicted by Kaplan-Meier plotter, and the related major pathways were analyzed through GO analysis and GSEA. PSMB1-related gene mutations and Tumor microenvironment characteristics were analyzed. The expression of PSMB1 in breast cancer tissues and cells were determined by RT-qPCR and IHC. MTT, colony formation assay, EdU, Transwell, wound healing assay and cell cycle assay were performed to observe its function in vitro. The western blot was conducted to detect its regulation on EMT markers and key proteins in PI3K pathway.
    RESULTS: In this study, PSMB1 was screened by CRISPR-Cas9 and identified to be upregulated in breast cancer samples. By further analysis, PSMB1 was found to be involved in tumor-related biological process and correlated with worse prognosis in breast cancer patients. In vitro experiments verified that downregulation of PSMB1 could inhibit the malignant phenotype of breast cancer cells. The western blot showed that si-PSMB1 significantly decreased the expression of key proteins and their phosphorylation form in PI3K-AKT-mTOR signaling.
    CONCLUSION: si-PSMB1 inhibited breast cancer cell proliferation, invasion and migration probably by targeting PI3K-AKT-mTOR signaling, which brings innovative mechanisms for breast cancer regulation and emerging ideas for therapeutic strategies.
    Keywords:  Breast cancer; CRISPR-Cas9; PI3K-AKT-mTOR signaling; PSMB1
    DOI:  https://doi.org/10.1007/s12672-026-05272-x
  3. Sci Rep. 2026 05 26. pii: 16296. [Epub ahead of print]16(1):
    Integrating network pharmacology with ex-vivo analysis to assess the effect of IL-2 in halting breast cancer: involvement of Treg/CTLA-4/Blimp-1/caspase-3.
    Seham Abou Shousha, Sherihan Salaheldin Abdelhamid Ibrahim, Hend Kadry, Eman Ahmed Youssef, Yasmine Qabany, Amira A Darwish, Atef Metwea, Suzan A Baheeg, Yasmine Shahine.
      The T lymphocytes have a vital role in tumor immunosurveillance within the tumor microenvironment (TME) but on the other hand, the TME adopts several mechanisms that cause inhibition and apoptosis to effector T cells leading to tumor immune evasion. The controversial role of interleukin-2 (IL-2) was demonstrated by promoting the activation and proliferation of different immune cells such as NK cells, effector and regulatory T cells (T regs). Thus, ex-vivo approach was used to investigate IL-2 anti-tumor effect on breast cancer cells isolated from Egyptian patients after mastectomy via modulating Treg/CTLA-4/Blimp-1/caspase-3 trajectory. Previous to the ex-vivo approach we aimed to find common targets between IL-2 and breast cancer disease using network pharmacology. Results of network pharmacology illustrated that there were 35 common targets including CD4, CTLA-4 and caspase 3. Breast cancers cells obtained were then cultured in the presence of 10 µl of (50 ng/ml) recombinant IL-2 for 24 h. Results revealed that tissue culture supplementation with IL-2 significantly reduced T regs within the TME via inhibiting the tumor expression of CD25 and Forkhead box P3 (FOXP3). In addition, it was found that IL-2 significantly decreased the expression of the inhibitory receptor CTLA-4 and increased the expression of B lymphocyte-induced maturation protein-1(Blimp-1), leading to the activation of effector T cells and the induction apoptosis of the breast tumor cells. These findings suggest that IL-2 could serve as a new treatment strategy for breast cancer via modulating immune responses within the TME.
    DOI:  https://doi.org/10.1038/s41598-026-52551-2
  4. Cell Biosci. 2026 May 28.
    Cannabidiol enhances tamoxifen efficacy via CREB-mediated suppression of ERα signaling in ER-positive breast cancer cells.
    Bu Gyeom Kim, Okhyeon Kim, Do-Yeon Lee, Bo Ram Kim, Dae Yeong Kim, Yoon Namgung, Jun Woo Bong, Sanghee Kang, Sun Il Lee, Sang Cheul Oh.
       BACKGROUND: Estrogen receptor alpha (ERα) plays a crucial role in the proliferation and survival of ER-positive breast cancer cells, and tamoxifen (TAM) remains the mainstay of endocrine therapy. However, acquired resistance to TAM remains a major clinical challenge. Despite advances in molecular profiling and targeted therapies, the mechanisms underlying TAM resistance remain incompletely understood. Emerging evidence suggest that dysregulation of intracellular signaling pathways, including the cAMP/CREB axis, may contribute to endocrine therapy failure.
    METHODS: We investigated the effects of cannabidiol (CBD) on TAM sensitivity and elucidated its underlying mechanisms in ER-positive breast cancer models. Human breast cancer cell lines (MCF7 and T47D) were treated with CBD, TAM or their combination. Apoptosis, proliferation, and protein expression were evaluated by flow cytometry, western blotting, and immunofluorescence. In vivo efficacy was examined in xenograft models.
    RESULTS: CBD significantly enhanced TAM-induced cell death and apoptosis in ER-positive breast cancer cell. Mechanistically, CBD suppressed the cAMP/CREB signaling pathway, leading to downregulation of ERα and its target genes (TFF1, GREB1, CCND1). Co-immunoprecipitation revealed that CBD inhibited the interaction between phosphorylated CREB and CBP, resulting in transcriptional suppression of ERα. In vivo, combined treatment with CBD and TAM synergistically inhibited tumor growth and reduced ERα and p-CREB expression levels in tumor tissues.
    CONCLUSIONS: Our findings demonstrate that CBD restores TAM sensitivity through CREB-mediated downregulation of ERα signaling in ER-positive breast cancer. This study suggests the potential application of CBD as a novel adjuvant agent to overcome TAM resistance and improve therapeutic outcomes in patients with ER-positive breast cancer.
    DOI:  https://doi.org/10.1186/s13578-026-01588-x
  5. Cell Biol Int. 2026 Jun;50(6): e70169
    Tamoxifen Modulates Actin Stress Fibre Dynamics Through c-Src-MLCK Signalling in Breast Cancer Cells.
    Bidisha Biswas, Shahnawaz Ahmed, Sowmya Manickavasagan, Akshay Jitendra Chaudhari, Sudhagar Selvaraju.
      Emerging evidence suggests that cytoskeletal dynamics are critical in drug resistance and metastasis. The present study investigates the influence of tamoxifen on actin stress fibre organisation in breast cancer cells. We demonstrate that tamoxifen treatment induces significant morphological changes, including increased cell spreading and polarity and enhanced migratory potential in breast cancer cells T47D and ZR-75-1. A loss of organised actin stress fibres and the emergence of lamellipodia and filopodia by tamoxifen treatment indicate its direct role in actin cytoskeleton remodelling, which was further confirmed by western blot analyses of key actin regulators. Upstream tamoxifen activates c-Src kinase, while reducing phosphorylation of myosin light chain (MLC), a key stress fibre regulator that activates myosin II. Further, inhibition of c-Src kinase with PP2 or silencing using siRNA reversed tamoxifen-induced stress fibre loss, confirming c-Src's pivotal role in modulating actin dynamics. These findings highlight a novel mechanism by which tamoxifen influences breast cancer cell actin dynamics and motility.
    Keywords:  actin stress fibre; breast cancer; c‐Src Kinase; myosin light chain; tamoxifen
    DOI:  https://doi.org/10.1002/cbin.70169
  6. Biomolecules. 2026 May 05. pii: 682. [Epub ahead of print]16(5):
    Exosomal MicroRNAs as Drivers of Desmoplasia and Treatment Resistance in Breast Cancer: Mechanisms, Biomarker Potential, and Therapeutic Opportunities.
    Jun Chung, Young Hwa Soung.
      Exosomal microRNAs (miRNAs) are key mediators of intercellular communication in the breast cancer tumor microenvironment (TME), facilitating bidirectional signaling between malignant cells and the desmoplastic stroma. This review explores current evidence on their dual roles as drivers of stromal remodeling and as circulating biomarkers of therapeutic resistance across major breast cancer subtypes, including triple-negative breast cancer (TNBC), hormone receptor-positive (ER+/PR+) disease, and HER2-amplified tumors. We outline how miR-9, miR-21, and miR-181 family members promote cancer-associated fibroblast (CAF) activation, increase extracellular matrix (ECM) stiffness, and sustain a reverse Warburg phenotype. We then detail subtype-specific resistance mechanisms: miR-181 family members suppress BCLAF1 to block doxorubicin-induced apoptosis; miR-221/222 downregulates ESR1 and p27Kip1 to confer tamoxifen resistance; miR-155 impairs homologous recombination in TNBC; and miR-1246 sustains PI3K/AKT signaling in HER2-positive disease. We also evaluate circulating exosomal miRNA panels as liquid biopsy tools for predicting chemotherapy response and tracking resistance emergence. Finally, we discuss therapeutic strategies including antagomirs, miRNA replacement therapy and engineered exosome platforms, and address key challenges such as assay standardization and regulatory hurdles, that must be overcome for clinical translation.
    Keywords:  breast cancer; cancer-associated fibroblasts; chemoresistance; desmoplasia; endocrine resistance; exosomes; liquid biopsy; mechanotransduction; miR-181 family; microRNA; triple-negative breast cancer; tumor microenvironment
    DOI:  https://doi.org/10.3390/biom16050682
  7. Int J Mol Sci. 2026 May 21. pii: 4633. [Epub ahead of print]27(10):
    CAFs and Endocrine Therapy Resistance in Hormone Receptor-Positive Breast Cancer.
    Amalia A Sofianidi, Vaia K Stafyla, Flora Zagouri.
      The development of endocrine resistance represents a major obstacle when treating hormone receptor-positive breast cancer. The tumor microenvironment (TME), represented by cancer-associated fibroblasts (CAFs) in this context, has recently been proposed as a key mediator significantly contributing to resistance against currently available endocrine therapies. The exact mechanisms behind this interaction are not fully understood; specific breast CAF subtypes have been linked to it, such as CAFs lacking the expression of the glycoprotein CD146 or maintaining the expression of CD63. Other proposed mechanisms include signaling pathways aberrantly activated in CAFs, epigenetic modifications mainly in the form of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), and paracrine signaling, all limiting endocrine modulation effectiveness. Strategies aiming to simultaneously target CAFs and endocrine signaling in luminal breast cancer are currently being developed. Fibroblast growth factor receptor (FGFR) targeting in combination with endocrine inhibition has already entered the clinical trial landscape. However, CAFs are a highly diverse and heterogeneous cell population, making their targeting complex and difficult to implement in clinical practice.
    Keywords:  CAFs; breast cancer; cancer-associated fibroblasts; endocrine resistance; luminal
    DOI:  https://doi.org/10.3390/ijms27104633
  8. Transl Cancer Res. 2026 Apr 30. 15(4): 294
    Mitochondrial gene APOO reprograms lipid metabolism to influence the prognosis of breast cancer.
    Yupeng Sha, Yi Du, Ming Niu, Quan Yuan, Jiguang Han.
       Background: Dynamics of mitochondrial metabolism are critical to breast cancer (BC) progression, yet the precise regulatory pathways underlying these changes remain incompletely understood. This study aimed to identify mitochondria-related prognostic genes in breast cancer, construct a mitochondria-related riskmodel, and investigate the role of apolipoprotein O (APOO) in lipid metabolic reprogramming and tumor progression.
    Methods: This study employed bioinformatics methods to identify highly active genes closely associated with mitochondrial metabolism, and conducted an in-depth analysis of their correlation with patient prognosis. By applying multiple machine learning algorithms, we developed a novel mitochondrial gene-related risk assessment model. Through functional gain-of-function and loss-of-function experiments in cell lines, we precisely characterized the functions of target genes. Furthermore, protein blotting techniques were utilized to investigate the underlying mechanisms.
    Results: This study revealed a potential correlation between APOO and prognosis in BC patients. Through receiver operating characteristic (ROC) curve analysis, we confirmed APOO's high diagnostic value [area under the curve (AUC) =0.906]. Further research demonstrated that APOO knockdown inhibited BC cell proliferation, anti-apoptotic capacity, and migration. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that APOO may regulate lipid metabolism reprogramming in BC. Ultimately, suppressing APOO expression preliminarily validated this correlation.
    Conclusions: Our research demonstrates that APOO serves as a biomarker for predicting prognosis in BC patients. APOO may influence BC progression through lipid metabolic reprogramming; however, the precise molecular mechanisms require further experimental validation. These findings suggest that APOO could represent a potential biomarker and therapeutic target for BC.
    Keywords:  APOO/MIC26; lipid metabolic reprogramming; machine learning; mitochondria-related genes; prognostic model
    DOI:  https://doi.org/10.21037/tcr-2025-aw-2554
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