bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2025–11–02
six papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. Targeting Ferroptosis as the Achilles' Heel of Breast Cancer: Mechanisms and Therapeutic Opportunities from a Comprehensive Systematic Review.
  2. Oncogenic Role of SAMD4B in Breast Cancer Progression by Activating Wnt/β-Catenin Pathway.
  3. CD44 knockdown and TGF‑β inhibition modulate cell proliferation and invasion in claudin‑low breast cancer cells.
  4. BMP1 Appears to be Involved in GPER1-mediated Progression and Tamoxifen Resistance of Luminal A Breast Cancer Cells.
  5. Cancer Manipulates Adjacent Adipose Tissue to Exploit Fatty Acids via HIF-1α/CCL2/PPARα Axis: A Metabolic Circuit to Support Tumor Progression.
  6. The role of TEAD4 gene in the Hippo signaling pathway in triple-negative breast cancer and targeted therapy strategies.
  1. Int J Mol Sci. 2025 Oct 11. pii: 9902. [Epub ahead of print]26(20):
    Targeting Ferroptosis as the Achilles' Heel of Breast Cancer: Mechanisms and Therapeutic Opportunities from a Comprehensive Systematic Review.
    Anna Szulc, Marta Woźniak.
      Ferroptosis, an iron-dependent form of regulated cell death marked by lipid peroxidation, has emerged as a promising therapeutic target in breast cancer, particularly in aggressive subtypes such as triple-negative breast cancer (TNBC). This systematic review explores the molecular mechanisms underlying ferroptosis sensitivity and resistance, focusing on the interplay between iron metabolism, antioxidant defenses, and tumor microenvironmental factors. Literature retrieved from PubMed and Scopus up to May was analyzed in accordance with PRISMA guidelines, including mechanistic studies, preclinical experiments, and ongoing clinical trials. Findings reveal that breast cancer cells evade ferroptosis through enhanced glutathione synthesis, upregulation of GPX4 and system Xc- and adaptive metabolic reprogramming; yet these same mechanisms create exploitable vulnerabilities, including dependence on cystine, polyunsaturated lipids, and dysregulated iron handling. Therapeutic strategies that target key ferroptosis regulators, such as GPX4, ACSL4, and SLC7A11, or that harness agents like statins, sulfasalazine, and nanoparticle-based iron complexes demonstrate strong potential to overcome chemoresistance and selectively eliminate therapy-resistant cancer cell populations. Taken together, the evidence highlights ferroptosis as a critical Achilles' heel of breast cancer biology and supports further clinical translation of ferroptosis-inducing therapies to improve outcomes in otherwise refractory breast cancer subtypes.
    Keywords:  breast cancer; chemoresistance; ferroptosis; iron metabolism; lipid peroxidation; metabolic reprogramming; therapeutic targeting; triple-negative breast cancer; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms26209902
  2. Biomolecules. 2025 Oct 07. pii: 1423. [Epub ahead of print]15(10):
    Oncogenic Role of SAMD4B in Breast Cancer Progression by Activating Wnt/β-Catenin Pathway.
    Jia-Hui Li, Xin-Ya Wang, Huan-Xi Song, Xiao-Fei Nie, Li-Na Zhang.
      The Sterile alpha motif domain-containing protein 4 (SAMD4) family consists of two evolutionarily conserved and highly homologous RNA-binding proteins, SAMD4A and SAMD4B. Previous studies have established SAMD4A as a tumor suppressor that is downregulated in breast cancer, while the function of SAMD4B in tumorigenesis remains poorly defined. In this study, we observed that SAMD4B expression is upregulated in breast cancer. Functional assays demonstrated that SAMD4B facilitated breast cancer cell proliferation, migration, and invasion by inducing epithelial-mesenchymal transition (EMT). Furthermore, SAMD4B accelerated G1-to-S phase cell cycle progression by modulating p53 expression, collectively supporting an oncogenic function of SAMD4B in breast cancer. Mechanistically, we found that SAMD4B enhanced TCF/LEF transcriptional activity and upregulated the expression of β-catenin, Cyclin D1, c-Myc, and Axin2. Further investigations confirmed that SAMD4B activated the Wnt/β-catenin pathway by stabilizing β-catenin mRNA and increasing β-catenin protein expression level. Importantly, treatment with XAV-939, a specific Wnt/β-catenin pathway inhibitor, abrogated the pro-oncogenic effects of SAMD4B overexpression, including Wnt/β-catenin pathway activation, enhanced proliferation, and increased metastatic capacity. These results confirm that SAMD4B promotes the malignant phenotypes of breast cancer cells in a manner dependent on the Wnt/β-catenin pathway. In summary, our findings clarify that SAMD4B exerts an oncogenic role in breast cancer progression by activating the Wnt/β-catenin pathway. These data identify SAMD4B as a potential therapeutic target in breast cancer, although further in vivo investigations are required to validate its clinical relevance.
    Keywords:  RNA-binding protein; SAMD4B; Wnt/β-catenin pathway; breast cancer; mRNA stability
    DOI:  https://doi.org/10.3390/biom15101423
  3. Oncol Rep. 2026 Jan;pii: 7. [Epub ahead of print]55(1):
    CD44 knockdown and TGF‑β inhibition modulate cell proliferation and invasion in claudin‑low breast cancer cells.
    Ryoichi Matsunuma, Kazuo Kinoshita, Sae Imada, Shoko Sato, Ryosuke Hayami, Michiko Tsuneizumi.
      CD44 serves a dual role in supporting tumor survival and promoting invasion. Claudin‑low breast cancer, characterized by a CD44+/CD24‑ phenotype and epithelial‑mesenchymal transition (EMT), displays aggressive behavior. The present study investigated the interaction between CD44 and TGF‑β signaling, and assessed the cellular effects of their combined inhibition. CD44 was knocked down in claudin‑low breast cancer cell lines (SUM159 and MDA‑MB‑231), and the TGF‑β receptor (TGFBR) inhibitor LY2109761 (LY‑61) was applied for treatment. Cell viability (MTT assay), apoptosis (annexin V assay), invasion (Transwell assay), colony formation and Smad2 phosphorylation (western blotting) were evaluated. CD44 knockdown reduced viability and increased apoptosis but did not markedly suppress invasion. Although TGF‑β stimulation enhanced Smad2 phosphorylation, CD44 knockdown alone did not increase Smad2 activation, indicating that it does not directly regulate Smad2. However, LY‑61 inhibited TGF‑β‑induced Smad2 phosphorylation, effectively counteracting pro‑invasive signaling. Notably, while CD44 knockdown alone had a negligible impact on invasion, its combination with LY‑61 markedly reduced the invasive capacity and colony formation of cells compared with the control (control cells transduced with non‑targeting short hairpin RNA without LY‑61 treatment). LY‑61 induced S phase accumulation, which was more pronounced in SUM159 cells than in MDA‑MB‑231 cells, indicating cell line‑specific effects on cell‑cycle regulation. Clinical data indicated that low CD44 expression was associated with improved survival in patients with claudin‑low breast cancer, despite its potential to enhance EMT signaling. These findings suggested that CD44 knockdown enhanced the response to TGFBR inhibition. Although CD44 depletion may increase EMT‑related signaling, invasion was primarily suppressed by TGF‑β blockade, and the combination with CD44 knockdown further enhanced the inhibition of proliferative phenotypes compared with either treatment alone. This dual‑targeting approach warrants further investigation in claudin‑low breast cancer.
    Keywords:  CD44; TGF‑β; claudin‑low breast cancer
    DOI:  https://doi.org/10.3892/or.2025.9012
  4. Cancer Genomics Proteomics. 2025 Nov-Dec;22(6):22(6): 900-911
    BMP1 Appears to be Involved in GPER1-mediated Progression and Tamoxifen Resistance of Luminal A Breast Cancer Cells.
    Katharina Wert, Johanna Jentsch, Julia Gallwas, Carsten Gründker.
       BACKGROUND/AIM: Bone morphogenetic protein 1 (BMP1) plays a role in the activation of both transforming growth factor-β (TGFβ) and BMP signaling pathways. We investigated whether BMP1 is involved in G-protein coupled estrogen receptor 1 (GPER1)-regulated progression of luminal A-type breast cancer cells.
    MATERIALS AND METHODS: Publicly available transcriptomic data from MCF7 breast cancer cells treated with the selective GPER1 agonist G1 were analyzed and the results, in particular the altered BMP1 expression, were validated by qPCR. Signs of epithelial-mesenchymal transition (EMT) were visualized by immune cytology. Invasion was quantified by modified Boyden chamber assay. Tamoxifen-resistant sublines of the MCF7 and T47D cell lines were established.
    RESULTS: Activation of GPER1 by the agonist G1 increased the expression of BMP1 in MCF7 and T47D luminal A breast cancer cells. In addition, EMT and invasion was enhanced after GPER1 activation. This effect could be prevented in part by the BMP1 inhibitor UK383367. Tamoxifen-resistant MCF7-TR and T47D-TR cells exhibited higher BMP1 expression, signs of EMT and enhanced invasiveness compared to their tamoxifen-sensitive wild type. Blocking GPER1 in MCF7-TR and T47D-TR cells using the antagonist G36 led to reduction in BMP1 expression, a slight decrease in EMT, reduced cell invasion, and increased sensitivity to tamoxifen.
    CONCLUSION: BMP1 appears to be involved in GPER1-mediated progression of luminal A breast cancer cells. In addition, BMP1 may play a role in tamoxifen-resistance.
    Keywords:  BMP1; Bone morphogenetic protein 1; G-protein coupled estrogen receptor 1; GPER1; luminal A breast cancer; tamoxifen-resistance
    DOI:  https://doi.org/10.21873/cgp.20546
  5. Adv Sci (Weinh). 2025 Oct 29. e15186
    Cancer Manipulates Adjacent Adipose Tissue to Exploit Fatty Acids via HIF-1α/CCL2/PPARα Axis: A Metabolic Circuit to Support Tumor Progression.
    Jeong-Eun Yun, Jieun Seo, Jiwon Koh, Seock-Ah Im, Ki Yong Hong, Yeseon Son, Do-Won Jeong, Junji Fukuda, Jong-Wan Park, Yang-Sook Chun.
      Rising obesity rates are closely linked to higher risk of cancer, yet the underlying mechanisms are not fully understood. It is previously reported that fatty acids (FAs) released from cancer-associated adipose tissue enhance hypoxia-inducible factor-1α (HIF-1α) expression in cancer cells, promoting tumor progression. Here, it is elucidated that cancer cells manipulate adjacent adipose tissue by secreting C-C chemokine ligand2 (CCL2) to exploit FAs. Activation of HIF-1α induced by FA influx increases CCL2 expression in cancer cells, which subsequently leads to lipolysis in nearby adipose tissue by activating peroxisome proliferator-activated receptor alpha (PPARα) signaling. This activation in adipose tissue results in the release of FAs into the tumor microenvironment. The increased lipid supply to tumor reactivates the FA/HIF-1α/CCL2 axis in cancer cells, further accelerating tumor growth and CCL2 secretion. This establishes a positive feedback loop between tumor and adjacent adipose tissue, which enhances cancer progression. This crosstalk is validated by using a polydimethylsiloxane-based 3D coculture system and in vivo models. In obese mice, this reciprocal signaling accelerated tumor progression, whereas intra-tumoral injection of CCL2-neutralizing antibody significantly suppressed it. These findings reveal a metabolic circuit for tumor survival and disrupting this interaction may provide promising therapeutic targets, particularly for obese cancer patients.
    Keywords:  CCL2; HIF‐1α; PPARα; cancer; obesity
    DOI:  https://doi.org/10.1002/advs.202515186
  6. BMC Med Genomics. 2025 Oct 30. 18(1): 172
    The role of TEAD4 gene in the Hippo signaling pathway in triple-negative breast cancer and targeted therapy strategies.
    Xueliang Zhang, Tao Wang, Xiaowen Lian, Changsheng Wei, Dong Yan, Yan Liang.
       BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis and limited targeted therapies. The Hippo signaling pathway, critical in tumor progression, may harbor key genes influencing TNBC behavior. However, the specific genes and their clinical significance remain unclear.
    METHODS: We analyzed the GSE45827 dataset from the GEO database using differential gene expression analysis (DEG) and weighted gene co-expression network analysis (WGCNA) to identify TNBC-related genes. We enriched Hippo pathway-related genes from the MsigDB database and literature to identify candidate genes (HRGs) that may affect TNBC progression. The Boruta algorithm further screened for core genes, which were validated by immunohistochemistry in TNBC and other breast cancer tissues. Finally, we explored the biological and pharmacological significance of the target through drug prediction, molecular docking, molecular dynamics simulations, and in vitro experiments.
    RESULTS: DEG analysis identified 2,888 differentially expressed genes, and WGCNA yielded 276 TNBC-associated genes. Intersection analysis with 70 hypoxia-related genes (HRGs) revealed four key genes: TEAD4, WWTR1, AREG, and SOX11. TEAD4 was confirmed as the central gene influencing TNBC progression. Immunohistochemical results showed strong TEAD4 expression in TNBC tissues, with negligible expression in adjacent normal tissues or other breast cancer subtypes. Drug prediction and molecular docking identified irinotecan as a potential TEAD4-targeting agent. Molecular dynamics simulations confirmed the stable binding and favorable dynamics of the irinotecan-TEAD4 complex. Both TEAD4 knockdown and irinotecan treatment significantly suppressed TNBC cell migration and invasion. The combination of TEAD4 knockout and irinotecan produced a more pronounced inhibitory effect, underscoring the therapeutic potential of targeting TEAD4 in TNBC.
    CONCLUSIONS: Through comprehensive analysis, we identified TEAD4 as a key gene in TNBC with high expression specificity. Irinotecan may be a potential targeted drug for TEAD4, offering a new therapeutic strategy for TNBC and potentially improving patient outcomes. Further experimental verification is required.
    Keywords:  Hippo signaling pathway; Irinotecan; TEAD4; Targeted therapy; Triple-negative breast cancer
    DOI:  https://doi.org/10.1186/s12920-025-02245-x
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