bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2025–01–19
eight papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. MRPL24 drives breast cancer metastasis and stemness by targeting c-MYC, BRD4, and STAT3.
  2. JOSD2 promotes breast cancer metastasis by deubiquitinating and stabilizing SMAD4.
  3. RSL3 induces ferroptosis by activating the NF-κB signalling pathway to enhance the chemosensitivity of triple-negative breast cancer cells to paclitaxel.
  4. Transcription factor EB (TFEB) activity increases resistance of TNBC stem cells to metabolic stress.
  5. The Microenvironment in DCIS and Its Role in Disease Progression.
  6. Co-targeting of metabolism using dietary and pharmacologic approaches reduces breast cancer metastatic burden.
  7. Metabolic Reprogramming and Adaption in Breast Cancer Progression and Metastasis.
  8. Mechanisms of Regulation of Cell Fate in Breast Development and Cancer.
  1. 3 Biotech. 2025 Feb;15(2): 37
    MRPL24 drives breast cancer metastasis and stemness by targeting c-MYC, BRD4, and STAT3.
    Abdul Jamil Khan, Islam Uddin Khan, Shad Man, Shihao Liu, Gaowa Ailun, Manzar Abbas, Feng Zhang.
      The study aims to investigate the clinicopathological significance of MRPL24 in human cancers, with a particular focus on breast cancer (BC). Comprehensive bioinformatics analyses were conducted using data from The Cancer Genome Atlas (TCGA) and various advanced database, including cBioPortal, UALCAN, TIMER, Prognoscan, TISIDB, KM Plotter, and The Human Protein Atlas, to provide a detailed evaluation of MRPL55's role in cancer. The findings were further validated through experimental studies. Pan-cancer analysis of TCGA/ICGC data revealed significant amplification of MRPL24 across multiple cancer types, with the highest amplification rate of 60% observed in metastatic breast cancer. MRPL24 was found to be overexpressed in primary breast tumors, metastatic, and various molecular subtypes of breast cancer. High MRPL24 expression was associated with poor prognosis and lower survival rates in breast cancer patients. RT-PCR and western blot confirmed MRPL24 depletion in breast cancer cells. Knockdown of MRPL24 was shown to suppress proliferation, and clonogenic potential in breast cancer cells and inhibit cell migration. Additionally, MRPL24 depletion sensitized breast cancer cells to PD0325901 and 5-FU treatment. Mechanistic studies revealed that MRPL24 knock-down downregulates mRNA levels of oncogenic genes, including c-MYC, BRD4, WNT3, and STAT3. Positive correlations were observed between MRPL24 and key genes involved in ferroptosis regulation, such as ERBB2, ERBB3, GRB2, PIK3CA, AKT1, MAPK3, and MAPK1. Finally, through virtual screening and molecular dynamics simulations, we have identified three FDA-approved drugs with strong binding affinities and interactions with MRPL24. These findings underscore MRPL24's oncogenic role in breast cancer and suggest potential therapeutic strategies targeting this protein.
    Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-04196-z.
    Keywords:  Biomarker; Breast cancer; C-MYC; Chemo-resistance; Ferroptosis; MRPL24; Metastasis; Stemness
    DOI:  https://doi.org/10.1007/s13205-024-04196-z
  2. Biochem Pharmacol. 2025 Jan 08. pii: S0006-2952(25)00010-3. [Epub ahead of print] 116748
    JOSD2 promotes breast cancer metastasis by deubiquitinating and stabilizing SMAD4.
    Jiamin Du, Jiao Wang, Fujing Ge, Hongrui Ma, Hongdao Zhu, Jiangxia Du, Fangjie Yan, Qiaojun He, Bo Yang, Tao Yuan, Hong Zhu.
      Breast cancer is one of the most common malignant tumors among women worldwide, and its high degree of metastasis significantly impacts treatment effectiveness leading to poor prognosis. The potential molecular mechanisms underlying breast cancer metastasis remain to be further elucidated. In this study, via database analysis, we revealed that the deubiquitinase josephin domain containing 2 (JOSD2) was abnormally amplified in patients with metastatic breast cancer, and was significantly negatively correlated with patient prognosis. By integrating data from the Gene Expression Omnibus (GEO) database and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis, we found that the transforming growth factor beta (TGF-β) signaling pathway was significantly activated in breast cancer patients with increased JOSD2 expression. Further studies revealed that JOSD2 interacted with and stabilized SMAD family member 4 (SMAD4) by removing polyubiquitin chains. Inhibition of JOSD2 by RNA interference effectively inhibited the metastasis of breast cancer cells both in vitro and in vivo. In conclusion, our study not only reveals the role of JOSD2 in promoting breast cancer metastasis for the first time, but also indicates promising directions for the future development of deubiquitinase inhibitors, which could yield significant therapeutic benefits. Nevertheless extensive research and development are required to fully realize this potential.
    Keywords:  Breast cancer; Deubiquitinase; JOSD2; Metastasis; SMAD4
    DOI:  https://doi.org/10.1016/j.bcp.2025.116748
  3. Sci Rep. 2025 Jan 11. 15(1): 1654
    RSL3 induces ferroptosis by activating the NF-κB signalling pathway to enhance the chemosensitivity of triple-negative breast cancer cells to paclitaxel.
    Jialin Yuan, Cong Liu, Chengwei Jiang, Ning Liu, Zhaoying Yang, Hua Xing.
      Chemotherapy resistance in triple-negative breast cancer (TNBC) leads to poor therapeutic effects and a poor prognosis. Given that paclitaxel-based chemotherapy is the main treatment method for TNBC, enhancing its chemosensitivity has been a research focus. Induced ferroptosis of tumour cells has been proven to increase chemosensitivity, but its ability to sensitize TNBC cells to paclitaxel (PTX) is unknown. In our experiments, measurements of viability and proliferation validated the synergistic effect of PTX combined with RSL3 on TNBC cells. The accumulation of intracellular Fe2+ and lipid reactive oxygen species, as well as the expression of malondialdehyde, illustrated that RSL3 enhanced the chemosensitivity of TNBC to PTX by inducing ferroptosis. Through transcriptome sequencing, a series of differentially expressed genes were identified, in which the expression of cytokines, such as CXCLs, was significantly increased in the treatment group, and the effect of combination therapy on TNBC was enriched mainly in the NFκB signalling pathway. In subsequent validation experiments, the use of the NF-κB inhibitor BAY11-7082 reversed the inhibitory effects of PTX and RSL3 on TNBC cell activity. In a xenograft immunodeficient mouse model, the inhibitory effects of PTX and RSL3 on TNBC in vivo were further verified. Our research validated the synergistic effects of PTX and RSL3 both in vivo and in vitro, with RSL3 inducing ferroptosis by activating the NF-κB signalling pathway, thereby increasing the chemosensitivity of TNBC to PTX. This study provides new insights for improving the therapeutic efficacy of treatment strategies.
    Keywords:  Chemosensitivity; Ferroptosis; Triple-negative breast cancer
    DOI:  https://doi.org/10.1038/s41598-025-85774-w
  4. Life Sci Alliance. 2025 Mar;pii: e202302259. [Epub ahead of print]8(3):
    Transcription factor EB (TFEB) activity increases resistance of TNBC stem cells to metabolic stress.
    Milad Soleimani, Mark Duchow, Ria Goyal, Alexander Somma, Tamer S Kaoud, Kevin N Dalby, Jeanne Kowalski, S Gail Eckhardt, Carla Van Den Berg.
      Breast cancer stem cells (CSCs) are difficult to therapeutically target, but continued efforts are critical given their contribution to tumor heterogeneity and treatment resistance in triple-negative breast cancer. CSC properties are influenced by metabolic stress, but specific mechanisms are lacking for effective drug intervention. Our previous work on TFEB suggested a key function in CSC metabolism. Indeed, TFEB knockdown (KD) inhibited mammosphere formation in vitro and tumor initiation/growth in vivo. These phenotypic effects were accompanied by a decline in CD44high/CD24low cells. Glycolysis inhibitor 2-deoxy-D-glucose (2-DG) induced TFEB nuclear translocation, indicative of TFEB transcriptional activity. TFEB KD blunted, whereas TFEB (S142A) augmented 2-DG-driven unfolded protein response (UPR) mediators, notably BiP/HSPA5 and CHOP. Like TFEB KD, silencing BiP/HSPA5 inhibited CSC self-renewal, suggesting that TFEB augments UPR-related survival. Further studies showed that TFEB KD attenuated 2-DG-directed autophagy, suggesting a mechanism whereby TFEB protects CSCs against 2-DG-induced stress. Our data indicate that TFEB modulates CSC metabolic stress response via autophagy and UPR. These findings reveal the novel role of TFEB in regulating CSCs during metabolic stress in triple-negative breast cancer.
    DOI:  https://doi.org/10.26508/lsa.202302259
  5. Adv Exp Med Biol. 2025 ;1464 211-235
    The Microenvironment in DCIS and Its Role in Disease Progression.
    Mohammad Reza Roozitalab, Niki Prekete, Michael Allen, Richard P Grose, J Louise Jones.
      Ductal carcinoma in situ (DCIS) accounts for ~20% of all breast cancer diagnoses but whilst known to be a precursor of invasive breast cancer (IBC), evidence suggests only one in six patients will ever progress. A key challenge is to distinguish between those lesions that will progress and those that will remain indolent. Molecular analyses of neoplastic epithelial cells have not identified consistent differences between lesions that progressed and those that did not, and this has focused attention on the tumour microenvironment (ME).The DCIS ME is unique, complex and dynamic. Myoepithelial cells form the wall of the ductal-lobular tree and exhibit broad tumour suppressor functions. However, in DCIS they acquire phenotypic changes that bestow them with tumour promoter properties, an important evolution since they act as the primary barrier for invasion. Changes in the peri-ductal stromal environment also arise in DCIS, including transformation of fibroblasts into cancer-associated fibroblasts (CAFs). CAFs orchestrate other changes in the stroma, including the physical structure of the extracellular matrix (ECM) through altered protein synthesis, as well as release of a plethora of factors including proteases, cytokines and chemokines that remodel the ECM. CAFs can also modulate the immune ME as well as impact on tumour cell signalling pathways. The heterogeneity of CAFs, including recognition of anti-tumourigenic populations, is becoming evident, as well as heterogeneity of immune cells and the interplay between these and the adipocyte and vascular compartments. Knowledge of the impact of these changes is more advanced in IBC but evidence is starting to accumulate for a role in DCIS. Detailed in vitro, in vivo and tissue studies focusing on the interplay between DCIS epithelial cells and the ME should help to define features that can better predict DCIS behaviour.
    Keywords:  Adipocytes; CAF; DCIS; Extracellular matrix; Immune cells; Microenvironment; Myoepithelial cell
    DOI:  https://doi.org/10.1007/978-3-031-70875-6_12
  6. NPJ Breast Cancer. 2025 Jan 14. 11(1): 3
    Co-targeting of metabolism using dietary and pharmacologic approaches reduces breast cancer metastatic burden.
    Qianying Zuo, Jin Young Yoo, Erik R Nelson, Matthew J Sikora, Rebecca B Riggins, Zeynep Madak-Erdogan.
      Patients with metastatic breast cancer face reduced quality of life and increased mortality rates, necessitating more effective anti-cancer strategies. Building on previous research that identified metastatic-niche-specific metabolic vulnerabilities, we investigated how a ketogenic diet enhances estrogen receptor (ER)-positive liver metastatic breast cancer's response to Fulvestrant (Fulv) treatment. Using in vitro cell lines and in vivo xenograft metastasis mouse models, we examined the molecular mechanisms of combining ER targeting with a ketogenic diet. We found that Fulv treatment downregulates the ketogenesis pathway enzyme OXCT1, leading to β-hydroxybutyrate accumulation and decreased tumor cell viability. We also explored interactions between glucose, palmitic acid, and β-hydroxybutyric acid. These findings establish the molecular basis and clinical potential of a ketogenic diet to enhance Fulv efficacy in patients with ER+ liver metastatic breast cancer, potentially improving survival outcomes and quality of life in this population.
    DOI:  https://doi.org/10.1038/s41523-024-00715-6
  7. Adv Exp Med Biol. 2025 ;1464 347-370
    Metabolic Reprogramming and Adaption in Breast Cancer Progression and Metastasis.
    Qianying Zuo, Yibin Kang.
      Recent evidence has revealed that cancer is not solely driven by genetic abnormalities but also by significant metabolic dysregulation. Cancer cells exhibit altered metabolic demands and rewiring of cellular metabolism to sustain their malignant characteristics. Metabolic reprogramming has emerged as a hallmark of cancer, playing a complex role in breast cancer initiation, progression, and metastasis. The different molecular subtypes of breast cancer exhibit distinct metabolic genotypes and phenotypes, offering opportunities for subtype-specific therapeutic approaches. Cancer-associated metabolic phenotypes encompass dysregulated nutrient uptake, opportunistic nutrient acquisition strategies, altered utilization of glycolysis and TCA cycle intermediates, increased nitrogen demand, metabolite-driven gene regulation, and metabolic interactions with the microenvironment. The tumor microenvironment, consisting of stromal cells, immune cells, blood vessels, and extracellular matrix components, influences metabolic adaptations through modulating nutrient availability, oxygen levels, and signaling pathways. Metastasis, the process of cancer spread, involves intricate steps that present unique metabolic challenges at each stage. Successful metastasis requires cancer cells to navigate varying nutrient and oxygen availability, endure oxidative stress, and adapt their metabolic processes accordingly. The metabolic reprogramming observed in breast cancer is regulated by oncogenes, tumor suppressor genes, and signaling pathways that integrate cellular signaling with metabolic processes. Understanding the metabolic adaptations associated with metastasis holds promise for identifying therapeutic targets to disrupt the metastatic process and improve patient outcomes. This chapter explores the metabolic alterations linked to breast cancer metastasis and highlights the potential for targeted interventions in this context.
    Keywords:  Breast cancer; Circulating tumor cells (CTCs); Epithelial-mesenchymal transition (EMT); Metabolism; Metastasis; Metastatic colonization
    DOI:  https://doi.org/10.1007/978-3-031-70875-6_17
  8. Adv Exp Med Biol. 2025 ;1464 167-184
    Mechanisms of Regulation of Cell Fate in Breast Development and Cancer.
    Alexandra Van Keymeulen.
      This chapter focuses on the mechanisms of regulation of cell fate in breast development, occurring mainly after birth, as well as in breast cancer. First, we will review how the microenvironment of the breast, as well as external cues, plays a crucial role in mammary gland cell specification and will describe how it has been shown to reprogram non-mammary cells into mammary epithelial cells. Then we will focus on the transcription factors and master regulators which have been established to be determinant for basal (BC) and luminal cell (LC) identity, and will describe the experiments of ectopic expression or loss of function of these transcription factors which demonstrated that they were crucial for cell fate. We will also discuss how master regulators are involved in the fate choice of LCs between estrogen receptor (ER)-positive cells and ER- cells, which will give rise to alveolar cells upon pregnancy and lactation. We will describe how oncogene expression induces reprogramming and change of fate of mammary epithelial cells before tumor appearance, which could be an essential step in tumorigenesis. Finally, we will describe the involvement of master regulators of mammary epithelial cells in breast cancer.
    Keywords:  Breast cancer; Cell fate; Cell reprogramming; Change of fate; Mammary gland; Master regulators
    DOI:  https://doi.org/10.1007/978-3-031-70875-6_10
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