bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2024–12–15
six papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. Fibroblast Growth Factor Receptor 4 Promotes Triple-Negative Breast Cancer Progression via Regulating Fatty Acid Metabolism Through the AKT/RYR2 Signaling.
  2. FAK inhibition suppresses breast cancer progression via DNA methylation-mediated DAB2 gene reactivation.
  3. Adipocyte-derived fatty acid uptake induces obesity-related breast cancer progression: a review.
  4. Cancer-associated fibroblasts affect breast cancer cell sensitivity to chemotherapeutic agents by regulating NRBP2.
  5. Deciphering molecular drivers of lactate metabolic shift in mammalian cell cultures.
  6. Mechanisms of breast cancer metastasis: the role of extracellular matrix.
  1. Cancer Med. 2024 Dec;13(23): e70439
    Fibroblast Growth Factor Receptor 4 Promotes Triple-Negative Breast Cancer Progression via Regulating Fatty Acid Metabolism Through the AKT/RYR2 Signaling.
    Jinhui Ye, Song Wu, Qiang Quan, Feng Ye, Jinhui Zhang, Cailu Song, Yidan Fan, Huijiao Cao, Hailin Tang, Jianfu Zhao.
       BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Previous studies have found that fibroblast growth factor receptor 4 (FGFR4) plays a crucial role in tumor development and metastasis. However, the potential role and underlying mechanisms of FGFR4 in the progression of TNBC remain unclear.
    METHODS: Statistical analysis of FGFR4 expression data in public databases was used to reveal its role in TNBC. qRT-PCR was used to detect FGFR4 expression levels. The impact of FGFR4 level changes on TNBC cell proliferation was assessed using CCK-8 and colony formation assays, while Transwell invasion assays and JC-1 staining were employed to analyze the effects of FGFR4 level changes on the invasiveness and survival capability of TNBC cells. Differentially expressed genes were subjected to Gene Ontology, KEGG, and GSEA enrichment analyses to identify associated signaling pathways. Additionally, Oil Red O staining, fatty acid metabolite detection, and Western blot analysis were used to investigate the impact of FGFR4 and its inhibitor fisogatinib, as well as the AKT activator SC79, on the metabolic reprogramming of fatty acids in TNBC cells.
    RESULTS: FGFR4 was found to be upregulated in breast cancer and correlated with poorer patient outcomes. Inhibition of FGFR4 resulted in reduced cell growth and invasion in TNBC cells. It also led to increased lipid accumulation, upregulated lipid biosynthesis-related genes, and downregulated lipolysis-related genes. Mechanistically, FGFR4 inhibition suppressed the activation of the AKT/RYR2 signaling pathway. Reactivating the AKT pathway reversed the suppressive effects of FGFR4 inhibition on TNBC progression.
    CONCLUSION: Dysregulated FGFR4 activates the AKT/RYR2 axis, leading to tumor proliferation, invasion, and altered lipid metabolism in TNBC. FGFR4 inhibition could potentially serve as a novel therapeutic strategy for TNBC treatment.
    Keywords:  AKT; FGFR4; RyR2; TNBC; fatty acid metabolism
    DOI:  https://doi.org/10.1002/cam4.70439
  2. bioRxiv. 2024 Nov 25. pii: 2024.11.23.624992. [Epub ahead of print]
    FAK inhibition suppresses breast cancer progression via DNA methylation-mediated DAB2 gene reactivation.
    James M Murphy, Kyuho Jeong, Eun-Young Erin Ahn, Ssang-Taek Steve Lim.
      Epigenetic silencing of tumor suppressor genes is one of the main drivers of tumor progression. Without these tumor suppressors to reduce proliferation, tumor cells proliferate unchecked. Focal adhesion kinase (FAK) is a tyrosine kinase which is often upregulated in various tumors and promotes cell proliferation and migration. Recent studies have demonstrated that pharmacological or genetic FAK inhibition can reduce suppressive DNA methylation in vascular cells. Mechanistically, this is through nuclear FAK-mediated ubiquitination and proteasomal degradation of DNA methyltransferase 3A (DNMT3A). Treatment of breast cancer cell lines with FAK inhibitor (FAK-I) was able to reduce both FAK activity and DNMT3A protein expression. Further, global DNA methylation was reduced in breast cancer cell lines treated with FAK-I. This decrease in DNA methylation was correlated with decreased cell proliferation. We further showed that FAK-I reduced DNMT3A expression in breast cancer cells and that treatment with the proteasome inhibitor MG132 prevented loss of DNTM3A protein stability. To identify how FAK-I and DNMT3A loss could reduce breast cancer cell growth we compared RNA sequencing data from breast cancer cells treated with or without FAK-I or in shRNA DNMT3A knockdown. We have identified a potential tumor suppressor, DAB2, as being regulated by the nuclear FAK-DNMT3A axis. DAB2 is often downregulated in cancers and has been shown to play a vital role in switching TGFβ signaling from proliferative to apoptotic by altering TGFβRI binding partners. Immunoblotting and immunostaining indeed revealed that FAK-I and shDNMT3A could induce DAB2 protein expression. Further, FAK-I treatment showed efficacy in reducing tumor growth in vivo using the murine 4T1 tumor model. Immunostaining of 4T1 tumors showed FAK-I decreased DNMT3A, DNA methylation (5-methylcytosine, 5-mC), and increased DAB2 expression. Taken together, these data suggest that nuclear FAK-mediated regulation of DNMT3A can alter the epigenetic landscape and induce tumor suppressor gene expression.
    DOI:  https://doi.org/10.1101/2024.11.23.624992
  3. Mol Biol Rep. 2024 Dec 07. 52(1): 39
    Adipocyte-derived fatty acid uptake induces obesity-related breast cancer progression: a review.
    Selin Kisar Tunca, Resat Unal.
      Obesity is a metabolic disorder that occurs when excess energy taken into the body is stored as fat. It is known that this metabolic imbalance affects the development of other diseases such as cancer, cardiovascular diseases, insulin resistance, and diabetes. The main cellular component of adipose tissue is adipocytes, and the environmental interactions of adipocytes are important to study the mechanism of disorder formation. Breast tissue is rich in adipose tissue and obesity is known to be an important risk factor in the development of breast cancer. Altered adipogenesis and lipogenesis processes in adipocytes in breast tissue support tumor development through the transfer of fatty acids released from adipocytes. We believe that blending adipocyte biology with breast cancer development is important for investigating the mechanisms that regulate breast tumor malignant behavior and providing new targets for treatment. Fatty acids, which are an energy source for breast cancer cells, are discussed from molecular perspectives in this review.
    Keywords:  Adipocyte; Breast cancer; Fatty acid uptake; Lipid metabolism; Obesity
    DOI:  https://doi.org/10.1007/s11033-024-10139-x
  4. Toxicol Res (Camb). 2024 Dec;13(6): tfae204
    Cancer-associated fibroblasts affect breast cancer cell sensitivity to chemotherapeutic agents by regulating NRBP2.
    Xiaoyan Jin, Yong Chen, Gui Wang.
       Objective: To uncover the role of nuclear receptor-binding protein 2 (NRBP2) in cancer-associated fibroblasts (CAFs), and CAFmediated TAM sensitivity in breast cancer (BC).
    Methods: 10 pairs of matched tumor tissues and adjacent normal tissues were collected and CAFs and normal fibroblasts (NFs) were isolated. CCK-8 as well as colony formation assays showed the effects on cell growth. qPCR and Immunoblot showed the expression of NRBP2 in CAFs. FCM as well as Immunoblot assays exhibited the effects on cell apoptosis. Immunoblot further confirmed the mechanism.
    Results: CAFs contributed to BC cell growth. In addition, the expression of NRBP2 is downregulated in CAFs. NRBP2 suppressed CAF-induced resistance in BC cells. Further, NRBP2 expression in CAF group increased TAM induced apoptosis. Mechanically, NRBP2 in CAFs inhibited Akt pathway, therefore suppressed resistance in BC cells.
    Conclusion: CAFs affected BC cell sensitivity to TAM by regulating NRBP2.
    Keywords:  Akt pathway; Breast cancer (BC); Cancer-associated fibroblasts (CAFs); Nuclear receptor-binding protein 2 (NRBP2); TAM
    DOI:  https://doi.org/10.1093/toxres/tfae204
  5. Metab Eng. 2024 Dec 04. pii: S1096-7176(24)00164-2. [Epub ahead of print]88 25-39
    Deciphering molecular drivers of lactate metabolic shift in mammalian cell cultures.
    Mauro Torres, Ellie Hawke, Robyn Hoare, Rachel Scholey, Leon P Pybus, Alison Young, Andrew Hayes, Alan J Dickson.
      Lactate metabolism plays a critical role in mammalian cell bioprocessing, influencing cellular performance and productivity. The transition from lactate production to consumption, known as lactate metabolic shift, is highly beneficial and has been shown to extend culture lifespan and enhance productivity, yet its molecular drivers remain poorly understood. Here, we have explored the mechanisms that underpin this metabolic shift through two case studies, illustrating environmental- and genetic-driven factors. We characterised these study cases at process, metabolic and transcriptomic levels. Our findings indicate that glutamine depletion coincided with the timing of the lactate metabolic shift, significantly affecting cell growth, productivity and overall metabolism. Transcriptome analysis revealed dynamic regulation the ATF4 pathway, involved in the amino acid (starvation) response, where glutamine depletion activates ATF4 gene and its targets. Manipulating ATF4 expression through overexpression and knockdown experiments showed significant changes in metabolism of glutamine and lactate, impacting cellular performance. Overexpression of ATF4 increased cell growth and glutamine consumption, promoting a lactate metabolic shift. In contrast, ATF4 downregulation decreased cell proliferation and glutamine uptake, leading to production of lactate without any signs of lactate shift. These findings underscore a critical role for ATF4 in regulation of glutamine and lactate metabolism, related to phasic patterns of growth during CHO cell culture. This study offers unique insight into metabolic reprogramming during the lactate metabolic shift and the molecular drivers that determine cell status during culture.
    Keywords:  Biopharmaceuticals; CHO cells; Glutamine; Lactate metabolic shift; Metabolome; Transcriptome
    DOI:  https://doi.org/10.1016/j.ymben.2024.12.001
  6. Mol Cell Biochem. 2024 Dec 09.
    Mechanisms of breast cancer metastasis: the role of extracellular matrix.
    Rui Chen, Ranqi Zhang, Famin Ke, Xiurong Guo, Fancai Zeng, Qiuyu Liu.
      The components of the extracellular matrix (ECM) are dynamic, and they mediate mechanical signals that modulate cellular behaviors. Disruption of the ECM can induce the migration and invasion of cancer cells via specific signaling pathways and cytokines. Metastasis is a leading cause of high mortality in malignancies, and early intervention can improve survival rates. However, breast cancer is frequently diagnosed subsequent to metastasis, resulting in poor prognosis and distant metastasis poses substantial hurdles in therapy. In breast cancer, there is notable tissue remodeling of ECM proteins, with several identified as essential components for metastasis. Moreover, specific ECM molecules, receptors, enzymes, and various signaling pathways play crucial roles in breast cancer metastasis, drug treatment, and resistance. The in-depth consideration of these elements could provide potential therapeutic targets to enhance the survival rates and quality of life for breast cancer patients. This review explores the mechanisms by which alterations in the ECM contribute to breast cancer metastasis and discusses current clinical applications targeting ECM in breast cancer treatment, offering valuable perspectives for future ECM-based therapies.
    Keywords:  Breast cancer; ECM; Extracellular matrix; Mechanisms; Metastasis
    DOI:  https://doi.org/10.1007/s11010-024-05175-x
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